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Sikiric P, Boban Blagaic A, Strbe S, Beketic Oreskovic L, Oreskovic I, Sikiric S, Staresinic M, Sever M, Kokot A, Jurjevic I, Matek D, Coric L, Krezic I, Tvrdeic A, Luetic K, Batelja Vuletic L, Pavic P, Mestrovic T, Sjekavica I, Skrtic A, Seiwerth S. The Stable Gastric Pentadecapeptide BPC 157 Pleiotropic Beneficial Activity and Its Possible Relations with Neurotransmitter Activity. Pharmaceuticals (Basel) 2024; 17:461. [PMID: 38675421 PMCID: PMC11053547 DOI: 10.3390/ph17040461] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2024] [Revised: 03/24/2024] [Accepted: 03/28/2024] [Indexed: 04/28/2024] Open
Abstract
We highlight the particular aspects of the stable gastric pentadecapeptide BPC 157 pleiotropic beneficial activity (not destroyed in human gastric juice, native and stable in human gastric juice, as a cytoprotection mediator holds a response specifically related to preventing or recovering damage as such) and its possible relations with neurotransmitter activity. We attempt to resolve the shortage of the pleiotropic beneficial effects of BPC 157, given the general standard neurotransmitter criteria, in classic terms. We substitute the lack of direct conclusive evidence (i.e., production within the neuron or present in it as a precursor molecule, released eliciting a response on the receptor on the target cells on neurons and being removed from the site of action once its signaling role is complete). This can be a network of interconnected evidence, previously envisaged in the implementation of the cytoprotection effects, consistent beneficial particular evidence that BPC 157 therapy counteracts dopamine, serotonin, glutamate, GABA, adrenalin/noradrenalin, acetylcholine, and NO-system disturbances. This specifically includes counteraction of those disturbances related to their receptors, both blockade and over-activity, destruction, depletion, tolerance, sensitization, and channel disturbances counteraction. Likewise, BPC 157 activates particular receptors (i.e., VGEF and growth hormone). Furthermore, close BPC 157/NO-system relations with the gasotransmitters crossing the cell membrane and acting directly on molecules inside the cell may envisage particular interactions with receptors on the plasma membrane of their target cells. Finally, there is nerve-muscle relation in various muscle disturbance counteractions, and nerve-nerve relation in various encephalopathies counteraction, which is also exemplified specifically by the BPC 157 therapy application.
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Affiliation(s)
- Predrag Sikiric
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (A.B.B.); (S.S.); (L.B.O.); (I.O.); (S.S.); (M.S.); (M.S.); (A.K.); (I.J.); (D.M.); (L.C.); (I.K.); (A.T.); (K.L.); (L.B.V.); (P.P.); (T.M.); (I.S.); (S.S.)
| | - Alenka Boban Blagaic
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (A.B.B.); (S.S.); (L.B.O.); (I.O.); (S.S.); (M.S.); (M.S.); (A.K.); (I.J.); (D.M.); (L.C.); (I.K.); (A.T.); (K.L.); (L.B.V.); (P.P.); (T.M.); (I.S.); (S.S.)
| | - Sanja Strbe
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (A.B.B.); (S.S.); (L.B.O.); (I.O.); (S.S.); (M.S.); (M.S.); (A.K.); (I.J.); (D.M.); (L.C.); (I.K.); (A.T.); (K.L.); (L.B.V.); (P.P.); (T.M.); (I.S.); (S.S.)
| | - Lidija Beketic Oreskovic
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (A.B.B.); (S.S.); (L.B.O.); (I.O.); (S.S.); (M.S.); (M.S.); (A.K.); (I.J.); (D.M.); (L.C.); (I.K.); (A.T.); (K.L.); (L.B.V.); (P.P.); (T.M.); (I.S.); (S.S.)
| | - Ivana Oreskovic
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (A.B.B.); (S.S.); (L.B.O.); (I.O.); (S.S.); (M.S.); (M.S.); (A.K.); (I.J.); (D.M.); (L.C.); (I.K.); (A.T.); (K.L.); (L.B.V.); (P.P.); (T.M.); (I.S.); (S.S.)
| | - Suncana Sikiric
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (A.B.B.); (S.S.); (L.B.O.); (I.O.); (S.S.); (M.S.); (M.S.); (A.K.); (I.J.); (D.M.); (L.C.); (I.K.); (A.T.); (K.L.); (L.B.V.); (P.P.); (T.M.); (I.S.); (S.S.)
- Department of Pathology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia
| | - Mario Staresinic
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (A.B.B.); (S.S.); (L.B.O.); (I.O.); (S.S.); (M.S.); (M.S.); (A.K.); (I.J.); (D.M.); (L.C.); (I.K.); (A.T.); (K.L.); (L.B.V.); (P.P.); (T.M.); (I.S.); (S.S.)
- Department of Surgery, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia
| | - Marko Sever
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (A.B.B.); (S.S.); (L.B.O.); (I.O.); (S.S.); (M.S.); (M.S.); (A.K.); (I.J.); (D.M.); (L.C.); (I.K.); (A.T.); (K.L.); (L.B.V.); (P.P.); (T.M.); (I.S.); (S.S.)
- Department of Surgery, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia
| | - Antonio Kokot
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (A.B.B.); (S.S.); (L.B.O.); (I.O.); (S.S.); (M.S.); (M.S.); (A.K.); (I.J.); (D.M.); (L.C.); (I.K.); (A.T.); (K.L.); (L.B.V.); (P.P.); (T.M.); (I.S.); (S.S.)
- Department of Anatomy and Neuroscience, School of Medicine, J.J. Strossmayer University of Osijek, 31000 Osijek, Croatia
| | - Ivana Jurjevic
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (A.B.B.); (S.S.); (L.B.O.); (I.O.); (S.S.); (M.S.); (M.S.); (A.K.); (I.J.); (D.M.); (L.C.); (I.K.); (A.T.); (K.L.); (L.B.V.); (P.P.); (T.M.); (I.S.); (S.S.)
| | - Danijel Matek
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (A.B.B.); (S.S.); (L.B.O.); (I.O.); (S.S.); (M.S.); (M.S.); (A.K.); (I.J.); (D.M.); (L.C.); (I.K.); (A.T.); (K.L.); (L.B.V.); (P.P.); (T.M.); (I.S.); (S.S.)
| | - Luka Coric
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (A.B.B.); (S.S.); (L.B.O.); (I.O.); (S.S.); (M.S.); (M.S.); (A.K.); (I.J.); (D.M.); (L.C.); (I.K.); (A.T.); (K.L.); (L.B.V.); (P.P.); (T.M.); (I.S.); (S.S.)
| | - Ivan Krezic
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (A.B.B.); (S.S.); (L.B.O.); (I.O.); (S.S.); (M.S.); (M.S.); (A.K.); (I.J.); (D.M.); (L.C.); (I.K.); (A.T.); (K.L.); (L.B.V.); (P.P.); (T.M.); (I.S.); (S.S.)
| | - Ante Tvrdeic
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (A.B.B.); (S.S.); (L.B.O.); (I.O.); (S.S.); (M.S.); (M.S.); (A.K.); (I.J.); (D.M.); (L.C.); (I.K.); (A.T.); (K.L.); (L.B.V.); (P.P.); (T.M.); (I.S.); (S.S.)
| | - Kresimir Luetic
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (A.B.B.); (S.S.); (L.B.O.); (I.O.); (S.S.); (M.S.); (M.S.); (A.K.); (I.J.); (D.M.); (L.C.); (I.K.); (A.T.); (K.L.); (L.B.V.); (P.P.); (T.M.); (I.S.); (S.S.)
| | - Lovorka Batelja Vuletic
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (A.B.B.); (S.S.); (L.B.O.); (I.O.); (S.S.); (M.S.); (M.S.); (A.K.); (I.J.); (D.M.); (L.C.); (I.K.); (A.T.); (K.L.); (L.B.V.); (P.P.); (T.M.); (I.S.); (S.S.)
- Department of Pathology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia
| | - Predrag Pavic
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (A.B.B.); (S.S.); (L.B.O.); (I.O.); (S.S.); (M.S.); (M.S.); (A.K.); (I.J.); (D.M.); (L.C.); (I.K.); (A.T.); (K.L.); (L.B.V.); (P.P.); (T.M.); (I.S.); (S.S.)
- Department of Surgery, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia
| | - Tomislav Mestrovic
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (A.B.B.); (S.S.); (L.B.O.); (I.O.); (S.S.); (M.S.); (M.S.); (A.K.); (I.J.); (D.M.); (L.C.); (I.K.); (A.T.); (K.L.); (L.B.V.); (P.P.); (T.M.); (I.S.); (S.S.)
- Department of Anatomy and Neuroscience, School of Medicine, J.J. Strossmayer University of Osijek, 31000 Osijek, Croatia
| | - Ivica Sjekavica
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (A.B.B.); (S.S.); (L.B.O.); (I.O.); (S.S.); (M.S.); (M.S.); (A.K.); (I.J.); (D.M.); (L.C.); (I.K.); (A.T.); (K.L.); (L.B.V.); (P.P.); (T.M.); (I.S.); (S.S.)
- Department of Diagnostic and Interventional Radiology, Sestre Milosrdnice University Hospital Center, 10000 Zagreb, Croatia
| | - Anita Skrtic
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (A.B.B.); (S.S.); (L.B.O.); (I.O.); (S.S.); (M.S.); (M.S.); (A.K.); (I.J.); (D.M.); (L.C.); (I.K.); (A.T.); (K.L.); (L.B.V.); (P.P.); (T.M.); (I.S.); (S.S.)
- Department of Pathology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia
| | - Sven Seiwerth
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (A.B.B.); (S.S.); (L.B.O.); (I.O.); (S.S.); (M.S.); (M.S.); (A.K.); (I.J.); (D.M.); (L.C.); (I.K.); (A.T.); (K.L.); (L.B.V.); (P.P.); (T.M.); (I.S.); (S.S.)
- Department of Pathology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia
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Sikiric P, Boban Blagaic A, Krezic I, Zizek H, Kalogjera L, Smoday IM, Vukovic V, Oroz K, Chiddenton HM, Buric S, Antunovic M, Gojkovic S, Strbe S, Skocic M, Sikiric S, Milavic M, Beketic Oreskovic L, Kokot A, Koprivanac A, Dobric I, Sever M, Staresinic M, Batelja Vuletic L, Skrtic A, Seiwerth S. From Selye's and Szabo's Cysteamine-Duodenal Ulcer in Rats to Dopamine in the Stomach: Therapy Significance and Possibilities. Pharmaceuticals (Basel) 2023; 16:1699. [PMID: 38139825 PMCID: PMC10748240 DOI: 10.3390/ph16121699] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2023] [Revised: 11/30/2023] [Accepted: 12/05/2023] [Indexed: 12/24/2023] Open
Abstract
We reviewed gastric ulcer healing by dopamine considering several distinctive duodenal key points. Selye and Szabo describe the cysteamine-induced duodenal ulcer in rats as a duodenal stress ulcer in patients. Szabo's cysteamine duodenal ulcer as the dopamine duodenal healing and cysteamine as a dopamine antagonist signifies the dopamine agonists anti-ulcer effect and dopamine antagonists ulcerogenic effect. From these viewpoints, we focused on dopamine and gastric ulcer healing. We mentioned antecedent studies on the dopamine presence in the stomach and gastric juice. Then we reviewed, in the timeline, therapy significance arising from the anti-ulcer potency of the various dopamine agonists, which is highly prevailing over the quite persistent beneficial evidence arising from the various dopamine antagonists. Meanwhile, the beneficial effects of several peptides (i.e., amylin, cholecystokinin, leptin, and stable gastric pentadecapeptide BPC 157, suggested as an acting mediator of the dopamine brain-gut axis) were included in the dopamine gastric ulcer story. We attempt to resolve dopamine agonists/antagonists issue with the dopamine significance in the stress (cysteamine as a prototype of the duodenal stress ulcer), and cytoprotection (cysteamine in small dose as a prototype of the cytoprotective agents; cysteamine duodenal ulcer in gastrectomized rats). Thereby, along with dopamine agonists' beneficial effects, in special circumstances, dopamine antagonists having their own ulcerogenic effect may act as "mild stress (or)" or "small irritant" counteracting subsequent strong alcohol or stress procedure-induced severe lesions in this particular tissue. Finally, in the conclusion, as a new improvement in further therapy, we emphasized the advantages of the dopamine agents' application in lower gastrointestinal tract therapy.
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Affiliation(s)
- Predrag Sikiric
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (A.B.B.); (I.K.); (H.Z.); (L.K.); (I.M.S.); (V.V.); (K.O.); (H.M.C.); (S.B.); (S.G.); (S.S.); (M.S.); (L.B.O.); (A.K.)
| | - Alenka Boban Blagaic
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (A.B.B.); (I.K.); (H.Z.); (L.K.); (I.M.S.); (V.V.); (K.O.); (H.M.C.); (S.B.); (S.G.); (S.S.); (M.S.); (L.B.O.); (A.K.)
| | - Ivan Krezic
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (A.B.B.); (I.K.); (H.Z.); (L.K.); (I.M.S.); (V.V.); (K.O.); (H.M.C.); (S.B.); (S.G.); (S.S.); (M.S.); (L.B.O.); (A.K.)
| | - Helena Zizek
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (A.B.B.); (I.K.); (H.Z.); (L.K.); (I.M.S.); (V.V.); (K.O.); (H.M.C.); (S.B.); (S.G.); (S.S.); (M.S.); (L.B.O.); (A.K.)
| | - Luka Kalogjera
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (A.B.B.); (I.K.); (H.Z.); (L.K.); (I.M.S.); (V.V.); (K.O.); (H.M.C.); (S.B.); (S.G.); (S.S.); (M.S.); (L.B.O.); (A.K.)
| | - Ivan Maria Smoday
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (A.B.B.); (I.K.); (H.Z.); (L.K.); (I.M.S.); (V.V.); (K.O.); (H.M.C.); (S.B.); (S.G.); (S.S.); (M.S.); (L.B.O.); (A.K.)
| | - Vlasta Vukovic
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (A.B.B.); (I.K.); (H.Z.); (L.K.); (I.M.S.); (V.V.); (K.O.); (H.M.C.); (S.B.); (S.G.); (S.S.); (M.S.); (L.B.O.); (A.K.)
| | - Katarina Oroz
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (A.B.B.); (I.K.); (H.Z.); (L.K.); (I.M.S.); (V.V.); (K.O.); (H.M.C.); (S.B.); (S.G.); (S.S.); (M.S.); (L.B.O.); (A.K.)
| | - Helen Marie Chiddenton
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (A.B.B.); (I.K.); (H.Z.); (L.K.); (I.M.S.); (V.V.); (K.O.); (H.M.C.); (S.B.); (S.G.); (S.S.); (M.S.); (L.B.O.); (A.K.)
| | - Sara Buric
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (A.B.B.); (I.K.); (H.Z.); (L.K.); (I.M.S.); (V.V.); (K.O.); (H.M.C.); (S.B.); (S.G.); (S.S.); (M.S.); (L.B.O.); (A.K.)
| | - Marko Antunovic
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (A.B.B.); (I.K.); (H.Z.); (L.K.); (I.M.S.); (V.V.); (K.O.); (H.M.C.); (S.B.); (S.G.); (S.S.); (M.S.); (L.B.O.); (A.K.)
| | - Slaven Gojkovic
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (A.B.B.); (I.K.); (H.Z.); (L.K.); (I.M.S.); (V.V.); (K.O.); (H.M.C.); (S.B.); (S.G.); (S.S.); (M.S.); (L.B.O.); (A.K.)
| | - Sanja Strbe
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (A.B.B.); (I.K.); (H.Z.); (L.K.); (I.M.S.); (V.V.); (K.O.); (H.M.C.); (S.B.); (S.G.); (S.S.); (M.S.); (L.B.O.); (A.K.)
| | - Milena Skocic
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (A.B.B.); (I.K.); (H.Z.); (L.K.); (I.M.S.); (V.V.); (K.O.); (H.M.C.); (S.B.); (S.G.); (S.S.); (M.S.); (L.B.O.); (A.K.)
| | - Suncana Sikiric
- Department of Pathology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (S.S.); (M.M.); (L.B.V.); (S.S.)
| | - Marija Milavic
- Department of Pathology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (S.S.); (M.M.); (L.B.V.); (S.S.)
| | - Lidija Beketic Oreskovic
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (A.B.B.); (I.K.); (H.Z.); (L.K.); (I.M.S.); (V.V.); (K.O.); (H.M.C.); (S.B.); (S.G.); (S.S.); (M.S.); (L.B.O.); (A.K.)
| | - Antonio Kokot
- Department of Anatomy and Neuroscience, Faculty of Medicine, Josip Juraj Strossmayer University of Osijek, 31000 Osijek, Croatia;
| | - Antun Koprivanac
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (A.B.B.); (I.K.); (H.Z.); (L.K.); (I.M.S.); (V.V.); (K.O.); (H.M.C.); (S.B.); (S.G.); (S.S.); (M.S.); (L.B.O.); (A.K.)
| | - Ivan Dobric
- Department of Surgery, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (I.D.); (M.S.)
| | - Marko Sever
- Department of Surgery, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (I.D.); (M.S.)
| | - Mario Staresinic
- Department of Surgery, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (I.D.); (M.S.)
| | - Lovorka Batelja Vuletic
- Department of Pathology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (S.S.); (M.M.); (L.B.V.); (S.S.)
| | - Anita Skrtic
- Department of Pathology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (S.S.); (M.M.); (L.B.V.); (S.S.)
| | - Sven Seiwerth
- Department of Pathology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (S.S.); (M.M.); (L.B.V.); (S.S.)
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Stable Gastric Pentadecapeptide BPC 157 and Striated, Smooth, and Heart Muscle. Biomedicines 2022; 10:biomedicines10123221. [PMID: 36551977 PMCID: PMC9775659 DOI: 10.3390/biomedicines10123221] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2022] [Revised: 11/29/2022] [Accepted: 12/01/2022] [Indexed: 12/14/2022] Open
Abstract
First, we review the definitively severed myotendinous junction and recovery by the cytoprotective stable gastric pentadecapeptide BPC 157 therapy, its healing that might combine both transected and detached tendon and transected muscle, ligament and bone injuries, applied alone, as native peptide therapy, effective in rat injury, given intraperitoneally or in drinking water or topically, at the site of injury. As a follow up, we reviewed that with the BPC 157 therapy, its cytoprotective ability to organize simultaneous healing of different tissues of and full recovery of the myotendinous junction might represent the particular muscle therapy against distinctive etiopathology muscle disabilities and weakness. In this, BPC 157 therapy might recover many of muscle disabilities (i.e., succinylcholine, vascular occlusion, spinal cord compression, stroke, traumatic brain injury, severe electrolyte disturbances, neurotoxins, neuroleptics, alcohol, serotonin syndrome and NO-system blockade and tumor-cachexia). These might provide practical realization of the multimodal muscle-axis impact able to react depending on the condition and the given agent(s) and the symptoms distinctively related to the prime injurious cause symptoms in the wide healing concept, the concept of cytoprotection, in particular. Further, the BPC 157 therapy might be the recovery for the disabled heart functioning, and disabled smooth muscle functioning (various sphincters function recovery). Finally, BPC 157, native and stable in human gastric juice, might be a prototype of anti-ulcer cytoprotective peptide for the muscle therapy with high curing potential (very safe profile (lethal dose not achieved), with suited wide effective range (µg-ng regimens) and ways of application).
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Novel Therapeutic Effects in Rat Spinal Cord Injuries: Recovery of the Definitive and Early Spinal Cord Injury by the Administration of Pentadecapeptide BPC 157 Therapy. Curr Issues Mol Biol 2022; 44:1901-1927. [PMID: 35678659 PMCID: PMC9164058 DOI: 10.3390/cimb44050130] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2022] [Revised: 04/22/2022] [Accepted: 04/24/2022] [Indexed: 12/17/2022] Open
Abstract
Recently, marked therapeutic effects pertaining to the recovery of injured rat spinal cords (1 min compression injury of the sacrocaudal spinal cord (S2-Co1) resulting in tail paralysis) appeared after a single intraperitoneal administration of the stable gastric pentadecapeptide BPC 157 at 10 min post-injury. Besides the demonstrated rapid and sustained recovery (1 year), we showed the particular points of the immediate effect of the BPC 157 therapy that began rapidly after its administration, (i) soon after injury (10 min), or (ii) later (4 days), in the rats with a definitive spinal cord injury. Specifically, in counteracting spinal cord hematoma and swelling, (i) in rats that had undergone acute spinal cord injury, followed by intraperitoneal BPC 157 application at 10 min, we focused on the first 10–30 min post-injury period (assessment of gross, microscopic, and gene expression changes). Taking day 4 post-injury as the definitive injury, (ii) we focused on the immediate effects after the BPC 157 intragastric application over 20 min of the post-therapy period. Comparable long-time recovery was noted in treated rats which had definitive tail paralysis: (iii) the therapy was continuously given per orally in drinking water, beginning at day 4 after injury and lasting one month after injury. BPC 157 rats presented only discrete edema and minimal hemorrhage and increased Nos1, Nos2, and Nos3 values (30 min post-injury, (i)) or only mild hemorrhage, and only discrete vacuolation of tissue (day 4, (ii)). In the day 4–30 post-injury study (iii), BPC 157 rats rapidly presented tail function recovery, and no demyelination process (Luxol fast blue staining).
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Tepes M, Gojkovic S, Krezic I, Zizek H, Vranes H, Madzar Z, Santak G, Batelja L, Milavic M, Sikiric S, Kocman I, Simonji K, Samara M, Knezevic M, Barisic I, Lovric E, Strbe S, Kokot A, Sjekavica I, Kolak T, Skrtic A, Seiwerth S, Boban Blagaic A, Sikiric P. Stable Gastric Pentadecapeptide BPC 157 Therapy for Primary Abdominal Compartment Syndrome in Rats. Front Pharmacol 2021; 12:718147. [PMID: 34966273 PMCID: PMC8710746 DOI: 10.3389/fphar.2021.718147] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2021] [Accepted: 11/17/2021] [Indexed: 12/14/2022] Open
Abstract
Recently, the stable gastric pentadecapeptide BPC 157 was shown to counteract major vessel occlusion syndromes, i.e., peripheral and/or central occlusion, while activating particular collateral pathways. We induced abdominal compartment syndrome (intra-abdominal pressure in thiopental-anesthetized rats at 25 mmHg (60 min), 30 mmHg (30 min), 40 mmHg (30 min), and 50 mmHg (15 min) and in esketamine-anesthetized rats (25 mmHg for 120 min)) as a model of multiple occlusion syndrome. By improving the function of the venous system with BPC 157, we reversed the chain of harmful events. Rats with intra-abdominal hypertension (grade III, grade IV) received BPC 157 (10 µg or 10 ng/kg sc) or saline (5 ml) after 10 min. BPC 157 administration recovered the azygos vein via the inferior–superior caval vein rescue pathway. Additionally, intracranial (superior sagittal sinus), portal, and caval hypertension and aortal hypotension were reduced, as were the grossly congested stomach and major hemorrhagic lesions, brain swelling, venous and arterial thrombosis, congested inferior caval and superior mesenteric veins, and collapsed azygos vein; thus, the failed collateral pathway was fully recovered. Severe ECG disturbances (i.e., severe bradycardia and ST-elevation until asystole) were also reversed. Microscopically, transmural hyperemia of the gastrointestinal tract, intestinal mucosa villi reduction, crypt reduction with focal denudation of superficial epithelia, and large bowel dilatation were all inhibited. In the liver, BPC 157 reduced congestion and severe sinusoid enlargement. In the lung, a normal presentation was observed, with no alveolar membrane focal thickening and no lung congestion or edema, and severe intra-alveolar hemorrhage was absent. Moreover, severe heart congestion, subendocardial infarction, renal hemorrhage, brain edema, hemorrhage, and neural damage were prevented. In conclusion, BPC 157 cured primary abdominal compartment syndrome.
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Affiliation(s)
- Marijan Tepes
- Department of Surgery, General Hospital Nasice, Nasice, Croatia
- Department of Clinical Medicine, Faculty of Dental Medicine and Health Osijek, Osijek, Croatia
- PhD Program Translational Research in Biomedicine—TRIBE, School of Medicine, University of Split, Split, Croatia
- Department of Pharmacology, School of Medicine, University of Zagreb, Zagreb, Croatia
| | - Slaven Gojkovic
- Department of Pharmacology, School of Medicine, University of Zagreb, Zagreb, Croatia
| | - Ivan Krezic
- Department of Pharmacology, School of Medicine, University of Zagreb, Zagreb, Croatia
| | - Helena Zizek
- Department of Pharmacology, School of Medicine, University of Zagreb, Zagreb, Croatia
| | - Hrvoje Vranes
- Department of Pharmacology, School of Medicine, University of Zagreb, Zagreb, Croatia
| | - Zrinko Madzar
- Clinical Department of Surgery, Sestre Milosrdnice University Hospital Center, Zagreb, Croatia
| | - Goran Santak
- Department of Surgery, Faculty of Medicine, University of Osijek, Osijek, Croatia
| | - Lovorka Batelja
- Department of Pathology, School of Medicine, University of Zagreb, Zagreb, Croatia
| | - Marija Milavic
- Department of Pathology, School of Medicine, University of Zagreb, Zagreb, Croatia
| | - Suncana Sikiric
- Department of Pathology, School of Medicine, University of Zagreb, Zagreb, Croatia
| | - Ivica Kocman
- Department of Pharmacology, School of Medicine, University of Zagreb, Zagreb, Croatia
| | - Karol Simonji
- Internal Diseases Clinic, Faculty of Veterinary Medicine Zagreb, Zagreb, Croatia
| | - Mariam Samara
- Department of Pharmacology, School of Medicine, University of Zagreb, Zagreb, Croatia
| | - Mario Knezevic
- Department of Pharmacology, School of Medicine, University of Zagreb, Zagreb, Croatia
| | - Ivan Barisic
- Department of Pharmacology, School of Medicine, University of Zagreb, Zagreb, Croatia
| | - Eva Lovric
- Department of Pathology, School of Medicine, University of Zagreb, Zagreb, Croatia
| | - Sanja Strbe
- Department of Pharmacology, School of Medicine, University of Zagreb, Zagreb, Croatia
| | - Antonio Kokot
- Department of Anatomy and Neuroscience, Faculty of Medicine, J.J. Strossmayer University of Osijek, Osijek, Croatia
| | - Ivica Sjekavica
- Department of Diagnostic and Interventional Radiology, University Hospital Centre, Zagreb, Croatia
| | - Toni Kolak
- Department of Surgery, School of Medicine, University of Zagreb, Zagreb, Croatia
| | - Anita Skrtic
- Department of Pathology, School of Medicine, University of Zagreb, Zagreb, Croatia
- *Correspondence: Predrag Sikiric, ; Anita Skrtic,
| | - Sven Seiwerth
- Department of Pathology, School of Medicine, University of Zagreb, Zagreb, Croatia
| | - Alenka Boban Blagaic
- Department of Pharmacology, School of Medicine, University of Zagreb, Zagreb, Croatia
| | - Predrag Sikiric
- Department of Pharmacology, School of Medicine, University of Zagreb, Zagreb, Croatia
- *Correspondence: Predrag Sikiric, ; Anita Skrtic,
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Deek SA. BPC 157 as Potential Treatment for COVID-19. Med Hypotheses 2021; 158:110736. [PMID: 34798584 PMCID: PMC8575535 DOI: 10.1016/j.mehy.2021.110736] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2021] [Revised: 10/07/2021] [Accepted: 11/03/2021] [Indexed: 02/07/2023]
Abstract
The emergence of coronavirus disease (COVID-19) in China at the end of 2019 has caused a large global outbreak. COVID-19 is largely seen as a thrombotic and vascular disease targeting endothelial cells (ECs) throughout the body that can provoke the breakdown of central vascular functions. This explains the complications and multi-organ failure seen in COVID-19 patients including acute respiratory distress syndrome, cardiovascular complications, liver damage, and neurological damage. Acknowledging the comorbidities and potential organ injuries throughout the course of COVID-19 is therefore crucial in the clinical management of patients. Here we discuss BPC 157, based primarily on animal model data, as a novel agent that can improve the clinical management of COVID-19. BPC 157 is a peptide that has demonstrated anti-inflammatory, cytoprotective, and endothelial-protective effects in different organ systems in different species. BPC 157 activated endothelial nitric oxide synthase (eNOS) is associated with nitric oxide (NO) release, tissue repair and angiomodulatory properties which can lead to improved vascular integrity and immune response, reduced proinflammatory profile, and reduced critical levels of the disease. As a result, discussion of its use as a potential prophylactic and complementary treatment is critical. All examined treatments, although potentiality effective against COVID-19, need either appropriate drug development or clinical trials in humans to be suitable for clinical use.
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Affiliation(s)
- Sarah A Deek
- Department of Civil, Architectural and Environmental Engineering, The University of Texas at Austin, 78712 Austin, TX, USA.
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Nasadyuk CM. Short peptide sequences: current knowledge and future prospects. UKRAINIAN BIOCHEMICAL JOURNAL 2021. [DOI: 10.15407/ubj93.05.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
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Japjec M, Horvat Pavlov K, Petrovic A, Staresinic M, Sebecic B, Buljan M, Vranes H, Giljanovic A, Drmic D, Japjec M, Prtoric A, Lovric E, Batelja Vuletic L, Dobric I, Boban Blagaic A, Skrtic A, Seiwerth S, Predrag S. Stable Gastric Pentadecapeptide BPC 157 as a Therapy for the Disable Myotendinous Junctions in Rats. Biomedicines 2021; 9:1547. [PMID: 34829776 PMCID: PMC8615275 DOI: 10.3390/biomedicines9111547] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2021] [Revised: 10/08/2021] [Accepted: 10/23/2021] [Indexed: 12/17/2022] Open
Abstract
(1) Aim: The stable gastric pentadecapeptide BPC 157 is known to heal transected muscle, tendon, and ligament. Thereby, in this study, we investigated the effect of BPC 157 on the dissection of the quadriceps tendon from the quadriceps muscle in rats. (2) Materials and Methods: Myotendinous junction defect, which cannot heal spontaneously in rats, as evidenced with consistent macro/microscopic, biomechanical, functional assessments, eNOS, and COX-2 mRNA levels and oxidative stress and NO-levels in the myotendinous junctions. BPC 157 (10 µg/kg, 10 ng/kg) regimen was given (i) intraperitoneally, first application immediately after surgery, last 24 h before sacrifice; (ii) per-orally, in drinking water (0.16 µg/mL, 0.16 ng/mL, 12 mL/rat/day), till the sacrifice at 7, 14, 28 and 42 postoperative days. (3) Results: These BPC 157 regimens document prominent therapy effects (macro/microscopic, biomechanical, functional much like eNOS and COX-2 mRNA levels and counteracted oxidative stress and NO-levels in the myotendinous junctions), while controls have a poor presentation. Especially, in rats with the disabled myotendinous junction, along with full functional recovery, BPC 157 counteracts muscle atrophy that is regularly progressive and brings muscle presentation close to normal. Accordingly, unlike the perilous course in controls, those rats, when receiving BPC 157 therapy, exhibit a smaller defect, and finally defects completely disappear. Microscopically, there are no more inflammatory infiltrate, well-oriented recovered tissue of musculotendon junction appears in BPC 157 treated rats at the 28 days and 42 days. (4) Conclusions: BPC 157 restores myotendinous junction in accordance with the healing of the transected muscle, tendon, and ligament.
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Affiliation(s)
- Mladen Japjec
- Department of Surgery, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (M.J.); (M.S.); (B.S.); (A.P.); (I.D.)
| | - Katarina Horvat Pavlov
- Department of Pathology, School of Medicine, University of Zagreb, P.O. Box 910, Salata 10, 10000 Zagreb, Croatia; (K.H.P.); (A.P.); (E.L.); (L.B.V.); (S.S.)
| | - Andreja Petrovic
- Department of Pathology, School of Medicine, University of Zagreb, P.O. Box 910, Salata 10, 10000 Zagreb, Croatia; (K.H.P.); (A.P.); (E.L.); (L.B.V.); (S.S.)
| | - Mario Staresinic
- Department of Surgery, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (M.J.); (M.S.); (B.S.); (A.P.); (I.D.)
| | - Bozidar Sebecic
- Department of Surgery, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (M.J.); (M.S.); (B.S.); (A.P.); (I.D.)
| | - Matko Buljan
- Department of Pharmacology, School of Medicine, University of Zagreb, P.O. Box, 916, Salata 11, 10000 Zagreb, Croatia; (M.B.); (H.V.); (A.G.); (D.D.); (M.J.); (A.B.B.)
| | - Hrvoje Vranes
- Department of Pharmacology, School of Medicine, University of Zagreb, P.O. Box, 916, Salata 11, 10000 Zagreb, Croatia; (M.B.); (H.V.); (A.G.); (D.D.); (M.J.); (A.B.B.)
| | - Ana Giljanovic
- Department of Pharmacology, School of Medicine, University of Zagreb, P.O. Box, 916, Salata 11, 10000 Zagreb, Croatia; (M.B.); (H.V.); (A.G.); (D.D.); (M.J.); (A.B.B.)
| | - Domagoj Drmic
- Department of Pharmacology, School of Medicine, University of Zagreb, P.O. Box, 916, Salata 11, 10000 Zagreb, Croatia; (M.B.); (H.V.); (A.G.); (D.D.); (M.J.); (A.B.B.)
| | - Miroslav Japjec
- Department of Pharmacology, School of Medicine, University of Zagreb, P.O. Box, 916, Salata 11, 10000 Zagreb, Croatia; (M.B.); (H.V.); (A.G.); (D.D.); (M.J.); (A.B.B.)
| | - Andreja Prtoric
- Department of Surgery, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (M.J.); (M.S.); (B.S.); (A.P.); (I.D.)
| | - Eva Lovric
- Department of Pathology, School of Medicine, University of Zagreb, P.O. Box 910, Salata 10, 10000 Zagreb, Croatia; (K.H.P.); (A.P.); (E.L.); (L.B.V.); (S.S.)
| | - Lovorka Batelja Vuletic
- Department of Pathology, School of Medicine, University of Zagreb, P.O. Box 910, Salata 10, 10000 Zagreb, Croatia; (K.H.P.); (A.P.); (E.L.); (L.B.V.); (S.S.)
| | - Ivan Dobric
- Department of Surgery, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (M.J.); (M.S.); (B.S.); (A.P.); (I.D.)
| | - Alenka Boban Blagaic
- Department of Pharmacology, School of Medicine, University of Zagreb, P.O. Box, 916, Salata 11, 10000 Zagreb, Croatia; (M.B.); (H.V.); (A.G.); (D.D.); (M.J.); (A.B.B.)
| | - Anita Skrtic
- Department of Pathology, School of Medicine, University of Zagreb, P.O. Box 910, Salata 10, 10000 Zagreb, Croatia; (K.H.P.); (A.P.); (E.L.); (L.B.V.); (S.S.)
| | - Sven Seiwerth
- Department of Pathology, School of Medicine, University of Zagreb, P.O. Box 910, Salata 10, 10000 Zagreb, Croatia; (K.H.P.); (A.P.); (E.L.); (L.B.V.); (S.S.)
| | - Sikiric Predrag
- Department of Pharmacology, School of Medicine, University of Zagreb, P.O. Box, 916, Salata 11, 10000 Zagreb, Croatia; (M.B.); (H.V.); (A.G.); (D.D.); (M.J.); (A.B.B.)
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Udovicic M, Sever M, Kavur L, Loncaric K, Barisic I, Balenovic D, Zivanovic Posilovic G, Strinic D, Uzun S, Batelja Vuletic L, Sikiric S, Skrtic A, Drmic D, Boban Blagaic A, Lovric Bencic M, Seiwerth S, Sikiric P. Stable Gastric Pentadecapeptide BPC 157 Therapy for Monocrotaline-Induced Pulmonary Hypertension in Rats Leads to Prevention and Reversal. Biomedicines 2021; 9:biomedicines9070822. [PMID: 34356886 PMCID: PMC8301325 DOI: 10.3390/biomedicines9070822] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2021] [Revised: 06/26/2021] [Accepted: 07/12/2021] [Indexed: 02/07/2023] Open
Abstract
Background. Monocrotaline selectively injures the lung's vascular endothelium and induces pulmonary arterial hypertension. The stable gastric pentadecapeptide BPC 157 acts as a prototype cytoprotective agent that maintains endothelium, and its application may be a novel therapy. Besides, BPC 157 prevents and reverses thrombosis formation, maintains platelet function, alleviates peripheral vascular occlusion disturbances, and has anti-arrhythmic and anti-inflammatory effects. Monocrotaline-induced pulmonary arterial hypertension in rats (wall thickness, total vessel area, heart frequency, QRS axis deviation, QT interval prolongation, increase in right ventricle systolic pressure and bodyweight loss) can be counteracted with early or delayed BPC 157 therapy. Methods and Results. After monocrotaline (80 mg/kg subcutaneously), BPC 157 (10 μg/kg or 10 ng/kg, days 1-14 or days 1-30 (early regimens), or days 14-30 (delayed regimen)) was given once daily intraperitoneally (last application 24 h before sacrifice) or continuously in drinking water until sacrifice (day 14 or 30). Without therapy, the outcome was the full monocrotaline syndrome, marked by right-side heart hypertrophy and massive thickening of the precapillary artery's smooth muscle layer, clinical deterioration, and sometimes death due to pulmonary hypertension and right-heart failure during the 4th week after monocrotaline injection. With all BPC 157 regimens, monocrotaline-induced pulmonary arterial hypertension (including all disturbed parameters) was counteracted, and consistent beneficial effects were documented during the whole course of the disease. Pulmonary hypertension was not even developed (early regimens) as quickly as the advanced pulmonary hypertension was rapidly attenuated and then completely eliminated (delayed regimen). Conclusions. Thus, pentadecapeptide BPC 157 prevents and counteracts monocrotaline-induced pulmonary arterial hypertension and cor pulmonale in rats.
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Affiliation(s)
- Mario Udovicic
- Department of Pharmacology, School of Medicine, University of Zagreb, Salata 11, P.O. Box 916, 10000 Zagreb, Croatia; (M.U.); (M.S.); (L.K.); (K.L.); (I.B.); (D.B.); (G.Z.P.); (D.S.); (S.U.); (D.D.); (A.B.B.); (M.L.B.)
| | - Marko Sever
- Department of Pharmacology, School of Medicine, University of Zagreb, Salata 11, P.O. Box 916, 10000 Zagreb, Croatia; (M.U.); (M.S.); (L.K.); (K.L.); (I.B.); (D.B.); (G.Z.P.); (D.S.); (S.U.); (D.D.); (A.B.B.); (M.L.B.)
| | - Lovro Kavur
- Department of Pharmacology, School of Medicine, University of Zagreb, Salata 11, P.O. Box 916, 10000 Zagreb, Croatia; (M.U.); (M.S.); (L.K.); (K.L.); (I.B.); (D.B.); (G.Z.P.); (D.S.); (S.U.); (D.D.); (A.B.B.); (M.L.B.)
| | - Kristina Loncaric
- Department of Pharmacology, School of Medicine, University of Zagreb, Salata 11, P.O. Box 916, 10000 Zagreb, Croatia; (M.U.); (M.S.); (L.K.); (K.L.); (I.B.); (D.B.); (G.Z.P.); (D.S.); (S.U.); (D.D.); (A.B.B.); (M.L.B.)
| | - Ivan Barisic
- Department of Pharmacology, School of Medicine, University of Zagreb, Salata 11, P.O. Box 916, 10000 Zagreb, Croatia; (M.U.); (M.S.); (L.K.); (K.L.); (I.B.); (D.B.); (G.Z.P.); (D.S.); (S.U.); (D.D.); (A.B.B.); (M.L.B.)
| | - Diana Balenovic
- Department of Pharmacology, School of Medicine, University of Zagreb, Salata 11, P.O. Box 916, 10000 Zagreb, Croatia; (M.U.); (M.S.); (L.K.); (K.L.); (I.B.); (D.B.); (G.Z.P.); (D.S.); (S.U.); (D.D.); (A.B.B.); (M.L.B.)
| | - Gordana Zivanovic Posilovic
- Department of Pharmacology, School of Medicine, University of Zagreb, Salata 11, P.O. Box 916, 10000 Zagreb, Croatia; (M.U.); (M.S.); (L.K.); (K.L.); (I.B.); (D.B.); (G.Z.P.); (D.S.); (S.U.); (D.D.); (A.B.B.); (M.L.B.)
| | - Dean Strinic
- Department of Pharmacology, School of Medicine, University of Zagreb, Salata 11, P.O. Box 916, 10000 Zagreb, Croatia; (M.U.); (M.S.); (L.K.); (K.L.); (I.B.); (D.B.); (G.Z.P.); (D.S.); (S.U.); (D.D.); (A.B.B.); (M.L.B.)
| | - Sandra Uzun
- Department of Pharmacology, School of Medicine, University of Zagreb, Salata 11, P.O. Box 916, 10000 Zagreb, Croatia; (M.U.); (M.S.); (L.K.); (K.L.); (I.B.); (D.B.); (G.Z.P.); (D.S.); (S.U.); (D.D.); (A.B.B.); (M.L.B.)
| | - Lovorka Batelja Vuletic
- Department of Pathology, School of Medicine, University of Zagreb, Salata 11, P.O. Box 916, 10000 Zagreb, Croatia; (L.B.V.); (S.S.); (S.S.)
| | - Suncana Sikiric
- Department of Pathology, School of Medicine, University of Zagreb, Salata 11, P.O. Box 916, 10000 Zagreb, Croatia; (L.B.V.); (S.S.); (S.S.)
| | - Anita Skrtic
- Department of Pathology, School of Medicine, University of Zagreb, Salata 11, P.O. Box 916, 10000 Zagreb, Croatia; (L.B.V.); (S.S.); (S.S.)
- Correspondence: (A.S.); (P.S.); Tel.: +385-1-4566-980 (A.S.); +385-1-4566-833 (P.S.); Fax: +385-1-4920-050 (A.S. & P.S.)
| | - Domagoj Drmic
- Department of Pharmacology, School of Medicine, University of Zagreb, Salata 11, P.O. Box 916, 10000 Zagreb, Croatia; (M.U.); (M.S.); (L.K.); (K.L.); (I.B.); (D.B.); (G.Z.P.); (D.S.); (S.U.); (D.D.); (A.B.B.); (M.L.B.)
| | - Alenka Boban Blagaic
- Department of Pharmacology, School of Medicine, University of Zagreb, Salata 11, P.O. Box 916, 10000 Zagreb, Croatia; (M.U.); (M.S.); (L.K.); (K.L.); (I.B.); (D.B.); (G.Z.P.); (D.S.); (S.U.); (D.D.); (A.B.B.); (M.L.B.)
| | - Martina Lovric Bencic
- Department of Pharmacology, School of Medicine, University of Zagreb, Salata 11, P.O. Box 916, 10000 Zagreb, Croatia; (M.U.); (M.S.); (L.K.); (K.L.); (I.B.); (D.B.); (G.Z.P.); (D.S.); (S.U.); (D.D.); (A.B.B.); (M.L.B.)
| | - Sven Seiwerth
- Department of Pathology, School of Medicine, University of Zagreb, Salata 11, P.O. Box 916, 10000 Zagreb, Croatia; (L.B.V.); (S.S.); (S.S.)
| | - Predrag Sikiric
- Department of Pharmacology, School of Medicine, University of Zagreb, Salata 11, P.O. Box 916, 10000 Zagreb, Croatia; (M.U.); (M.S.); (L.K.); (K.L.); (I.B.); (D.B.); (G.Z.P.); (D.S.); (S.U.); (D.D.); (A.B.B.); (M.L.B.)
- Correspondence: (A.S.); (P.S.); Tel.: +385-1-4566-980 (A.S.); +385-1-4566-833 (P.S.); Fax: +385-1-4920-050 (A.S. & P.S.)
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Seiwerth S, Milavic M, Vukojevic J, Gojkovic S, Krezic I, Vuletic LB, Pavlov KH, Petrovic A, Sikiric S, Vranes H, Prtoric A, Zizek H, Durasin T, Dobric I, Staresinic M, Strbe S, Knezevic M, Sola M, Kokot A, Sever M, Lovric E, Skrtic A, Blagaic AB, Sikiric P. Stable Gastric Pentadecapeptide BPC 157 and Wound Healing. Front Pharmacol 2021; 12:627533. [PMID: 34267654 PMCID: PMC8275860 DOI: 10.3389/fphar.2021.627533] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2020] [Accepted: 02/03/2021] [Indexed: 12/11/2022] Open
Abstract
Significance: The antiulcer peptide, stable gastric pentadecapeptide BPC 157 (previously employed in ulcerative colitis and multiple sclerosis trials, no reported toxicity (LD1 not achieved)), is reviewed, focusing on the particular skin wound therapy, incisional/excisional wound, deep burns, diabetic ulcers, and alkali burns, which may be generalized to the other tissues healing. Recent Advances: BPC 157 has practical applicability (given alone, with the same dose range, and same equipotent routes of application, regardless the injury tested). Critical Issues: By simultaneously curing cutaneous and other tissue wounds (colocutaneous, gastrocutaneous, esophagocutaneous, duodenocutaneous, vesicovaginal, and rectovaginal) in rats, the potency of BPC 157 is evident. Healing of the wounds is accomplished by resolution of vessel constriction, the primary platelet plug, the fibrin mesh which acts to stabilize the platelet plug, and resolution of the clot. Thereby, BPC 157 is effective in wound healing much like it is effective in counteracting bleeding disorders, produced by amputation, and/or anticoagulants application. Likewise, BPC 157 may prevent and/or attenuate or eliminate, thus, counteract both arterial and venous thrombosis. Then, confronted with obstructed vessels, there is circumvention of the occlusion, which may be the particular action of BPC 157 in ischemia/reperfusion. Future Directions: BPC 157 rapidly increases various genes expression in rat excision skin wound. This would define the healing in the other tissues, that is, gastrointestinal tract, tendon, ligament, muscle, bone, nerve, spinal cord, cornea (maintained transparency), and blood vessels, seen with BPC 157 therapy.
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Affiliation(s)
- Sven Seiwerth
- Department of Pathology, School of Medicine, University of Zagreb, Zagreb, Croatia
| | - Marija Milavic
- Department of Pathology, School of Medicine, University of Zagreb, Zagreb, Croatia
| | - Jaksa Vukojevic
- Department of Pharmacology, School of Medicine, University of Zagreb, Zagreb, Croatia
| | - Slaven Gojkovic
- Department of Pharmacology, School of Medicine, University of Zagreb, Zagreb, Croatia
| | - Ivan Krezic
- Department of Pharmacology, School of Medicine, University of Zagreb, Zagreb, Croatia
| | | | | | - Andrea Petrovic
- Department of Pathology, School of Medicine, University of Zagreb, Zagreb, Croatia
| | - Suncana Sikiric
- Department of Pathology, School of Medicine, University of Zagreb, Zagreb, Croatia
| | - Hrvoje Vranes
- Department of Pharmacology, School of Medicine, University of Zagreb, Zagreb, Croatia
| | - Andreja Prtoric
- Department of Surgery, School of Medicine, University of Zagreb, Zagreb, Croatia
| | - Helena Zizek
- Department of Pharmacology, School of Medicine, University of Zagreb, Zagreb, Croatia
| | - Tajana Durasin
- Department of Pharmacology, School of Medicine, University of Zagreb, Zagreb, Croatia
| | - Ivan Dobric
- Department of Surgery, School of Medicine, University of Zagreb, Zagreb, Croatia
| | - Mario Staresinic
- Department of Surgery, School of Medicine, University of Zagreb, Zagreb, Croatia
| | - Sanja Strbe
- Department of Pharmacology, School of Medicine, University of Zagreb, Zagreb, Croatia
| | - Mario Knezevic
- Department of Pharmacology, School of Medicine, University of Zagreb, Zagreb, Croatia
| | - Marija Sola
- Department of Pharmacology, School of Medicine, University of Zagreb, Zagreb, Croatia
| | - Antonio Kokot
- Department of Anatomy and Neuroscience, School of Medicine Osijek, University of Osijek, Osijek, Croatia
| | - Marko Sever
- Department of Surgery, School of Medicine, University of Zagreb, Zagreb, Croatia
| | - Eva Lovric
- Department of Pathology, School of Medicine, University of Zagreb, Zagreb, Croatia
| | - Anita Skrtic
- Department of Pathology, School of Medicine, University of Zagreb, Zagreb, Croatia
| | - Alenka Boban Blagaic
- Department of Pharmacology, School of Medicine, University of Zagreb, Zagreb, Croatia
| | - Predrag Sikiric
- Department of Pharmacology, School of Medicine, University of Zagreb, Zagreb, Croatia
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BPC 157 Therapy and the Permanent Occlusion of the Superior Sagittal Sinus in Rat: Vascular Recruitment. Biomedicines 2021; 9:biomedicines9070744. [PMID: 34203464 PMCID: PMC8301421 DOI: 10.3390/biomedicines9070744] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2021] [Revised: 05/28/2021] [Accepted: 06/04/2021] [Indexed: 12/13/2022] Open
Abstract
We show the complex syndrome of the occluded superior sagittal sinus, brain swelling and lesions and multiple peripheral organs lesions in rat. Recovery goes centrally and peripherally, with the stable gastric pentadecapeptide BPC 157, which alleviated peripheral vascular occlusion disturbances, rapidly activating alternative bypassing pathways. Assessments were gross recording, venography, ECG, pressure, microscopy, biochemistry. The increased pressure in the superior sagittal sinus, portal and caval hypertension, aortal hypotension, arterial and venous thrombosis, severe brain swelling and lesions (cortex (cerebral, cerebellar), hypothalamus/thalamus, hippocampus), particular veins (azygos, superior mesenteric, inferior caval) dysfunction, heart dysfunction, lung congestion as acute respiratory distress syndrome, kidney disturbances, liver failure, and hemorrhagic lesions in gastrointestinal tract were all assessed. Rats received BPC 157 medication (10 µg/kg, 10 ng/kg) intraperitoneally, intragastrically, or topically to the swollen brain at 1 min ligation-time, or at 15 min, 24 h and 48 h ligation-time. BPC 157 therapy rapidly attenuates the brain swelling, rapidly eliminates the increased pressure in the ligated superior sagittal sinus and the severe portal and caval hypertension and aortal hypotension, and rapidly recruits collateral vessels, centrally ((para)sagittal venous collateral circulation) and peripherally (left superior caval vein azygos vein-inferior caval vein). In conclusion, as shown by all assessments, BPC 157 acts against the permanent occlusion of the superior sagittal sinus and syndrome (i.e., brain, heart, lung, liver, kidney, gastrointestinal lesions, thrombosis), given at 1 min, 15 min, 24 h or 48 h ligation-time. BPC 157 therapy rapidly overwhelms the permanent occlusion of the superior sagittal sinus in rat.
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Knezevic M, Gojkovic S, Krezic I, Zizek H, Malekinusic D, Vrdoljak B, Vranes H, Knezevic T, Barisic I, Horvat Pavlov K, Drmic D, Staroveski M, Djuzel A, Rajkovic Z, Kolak T, Kocman I, Lovric E, Milavic M, Sikiric S, Tvrdeic A, Patrlj L, Strbe S, Kokot A, Boban Blagaic A, Skrtic A, Seiwerth S, Sikiric P. Occlusion of the Superior Mesenteric Artery in Rats Reversed by Collateral Pathways Activation: Gastric Pentadecapeptide BPC 157 Therapy Counteracts Multiple Organ Dysfunction Syndrome; Intracranial, Portal, and Caval Hypertension; and Aortal Hypotension. Biomedicines 2021; 9:biomedicines9060609. [PMID: 34073625 PMCID: PMC8229949 DOI: 10.3390/biomedicines9060609] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2021] [Revised: 05/17/2021] [Accepted: 05/18/2021] [Indexed: 12/13/2022] Open
Abstract
Gastric pentadecapeptide BPC 157 therapy counteracts multiple organ dysfunction syndrome in rats, which have permanent occlusion of the superior mesenteric artery close to the abdominal aorta. Previously, when confronted with major vessel occlusion, its effect would rapidly activate collateral vessel pathways and resolve major venous occlusion syndromes (Pringle maneuver ischemia, reperfusion, Budd-Chiari syndrome) in rats. This would overwhelm superior mesenteric artery permanent occlusion, and result in local, peripheral, and central disturbances. Methods: Assessments, for 30 min (gross recording, angiography, ECG, pressure, microscopy, biochemistry, and oxidative stress), included the portal hypertension, caval hypertension, and aortal hypotension, and centrally, the superior sagittal sinus hypertension; systemic arterial and venous thrombosis; ECG disturbances; MDA-tissue increase; and multiple organ lesions and disturbances, including the heart, lung, liver, kidney, and gastrointestinal tract, in particular, as well as brain (cortex (cerebral, cerebellar), hypothalamus/thalamus, hippocampus). BPC 157 therapy (/kg, abdominal bath) (10 µg, 10 ng) was given for a 1-min ligation time. Results: BPC 157 rapidly recruits collateral vessels (inferior anterior pancreaticoduodenal artery and inferior mesenteric artery) that circumvent occlusion and ascertains blood flow distant from the occlusion in the superior mesenteric artery. Portal and caval hypertension, aortal hypotension, and, centrally, superior sagittal sinus hypertension were attenuated or eliminated, and ECG disturbances markedly mitigated. BPC 157 therapy almost annihilated venous and arterial thrombosis. Multiple organ lesions and disturbances (i.e., heart, lung, liver, and gastrointestinal tract, in particular, as well as brain) were largely attenuated. Conclusions: Rats with superior mesenteric artery occlusion may additionally undergo BPC 157 therapy as full counteraction of vascular occlusion-induced multiple organ dysfunction syndrome.
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Affiliation(s)
- Mario Knezevic
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (M.K.); (S.G.); (I.K.); (H.Z.); (D.M.); (B.V.); (H.V.); (T.K.); (I.B.); (D.D.); (M.S.); (A.D.); (T.K.); (I.K.); (A.T.); (L.P.); (S.S.); (A.B.B.)
| | - Slaven Gojkovic
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (M.K.); (S.G.); (I.K.); (H.Z.); (D.M.); (B.V.); (H.V.); (T.K.); (I.B.); (D.D.); (M.S.); (A.D.); (T.K.); (I.K.); (A.T.); (L.P.); (S.S.); (A.B.B.)
| | - Ivan Krezic
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (M.K.); (S.G.); (I.K.); (H.Z.); (D.M.); (B.V.); (H.V.); (T.K.); (I.B.); (D.D.); (M.S.); (A.D.); (T.K.); (I.K.); (A.T.); (L.P.); (S.S.); (A.B.B.)
| | - Helena Zizek
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (M.K.); (S.G.); (I.K.); (H.Z.); (D.M.); (B.V.); (H.V.); (T.K.); (I.B.); (D.D.); (M.S.); (A.D.); (T.K.); (I.K.); (A.T.); (L.P.); (S.S.); (A.B.B.)
| | - Dominik Malekinusic
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (M.K.); (S.G.); (I.K.); (H.Z.); (D.M.); (B.V.); (H.V.); (T.K.); (I.B.); (D.D.); (M.S.); (A.D.); (T.K.); (I.K.); (A.T.); (L.P.); (S.S.); (A.B.B.)
| | - Borna Vrdoljak
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (M.K.); (S.G.); (I.K.); (H.Z.); (D.M.); (B.V.); (H.V.); (T.K.); (I.B.); (D.D.); (M.S.); (A.D.); (T.K.); (I.K.); (A.T.); (L.P.); (S.S.); (A.B.B.)
| | - Hrvoje Vranes
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (M.K.); (S.G.); (I.K.); (H.Z.); (D.M.); (B.V.); (H.V.); (T.K.); (I.B.); (D.D.); (M.S.); (A.D.); (T.K.); (I.K.); (A.T.); (L.P.); (S.S.); (A.B.B.)
| | - Tamara Knezevic
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (M.K.); (S.G.); (I.K.); (H.Z.); (D.M.); (B.V.); (H.V.); (T.K.); (I.B.); (D.D.); (M.S.); (A.D.); (T.K.); (I.K.); (A.T.); (L.P.); (S.S.); (A.B.B.)
| | - Ivan Barisic
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (M.K.); (S.G.); (I.K.); (H.Z.); (D.M.); (B.V.); (H.V.); (T.K.); (I.B.); (D.D.); (M.S.); (A.D.); (T.K.); (I.K.); (A.T.); (L.P.); (S.S.); (A.B.B.)
| | - Katarina Horvat Pavlov
- Department of Pathology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (K.H.P.); (E.L.); (M.M.); (S.S.); (A.S.); (S.S.)
| | - Domagoj Drmic
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (M.K.); (S.G.); (I.K.); (H.Z.); (D.M.); (B.V.); (H.V.); (T.K.); (I.B.); (D.D.); (M.S.); (A.D.); (T.K.); (I.K.); (A.T.); (L.P.); (S.S.); (A.B.B.)
| | - Miro Staroveski
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (M.K.); (S.G.); (I.K.); (H.Z.); (D.M.); (B.V.); (H.V.); (T.K.); (I.B.); (D.D.); (M.S.); (A.D.); (T.K.); (I.K.); (A.T.); (L.P.); (S.S.); (A.B.B.)
| | - Antonija Djuzel
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (M.K.); (S.G.); (I.K.); (H.Z.); (D.M.); (B.V.); (H.V.); (T.K.); (I.B.); (D.D.); (M.S.); (A.D.); (T.K.); (I.K.); (A.T.); (L.P.); (S.S.); (A.B.B.)
| | - Zoran Rajkovic
- Department of Surgery, Faculty of Dental Medicine and Health, University of Osijek, 31000 Osijek, Croatia;
| | - Toni Kolak
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (M.K.); (S.G.); (I.K.); (H.Z.); (D.M.); (B.V.); (H.V.); (T.K.); (I.B.); (D.D.); (M.S.); (A.D.); (T.K.); (I.K.); (A.T.); (L.P.); (S.S.); (A.B.B.)
| | - Ivica Kocman
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (M.K.); (S.G.); (I.K.); (H.Z.); (D.M.); (B.V.); (H.V.); (T.K.); (I.B.); (D.D.); (M.S.); (A.D.); (T.K.); (I.K.); (A.T.); (L.P.); (S.S.); (A.B.B.)
| | - Eva Lovric
- Department of Pathology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (K.H.P.); (E.L.); (M.M.); (S.S.); (A.S.); (S.S.)
| | - Marija Milavic
- Department of Pathology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (K.H.P.); (E.L.); (M.M.); (S.S.); (A.S.); (S.S.)
| | - Suncana Sikiric
- Department of Pathology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (K.H.P.); (E.L.); (M.M.); (S.S.); (A.S.); (S.S.)
| | - Ante Tvrdeic
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (M.K.); (S.G.); (I.K.); (H.Z.); (D.M.); (B.V.); (H.V.); (T.K.); (I.B.); (D.D.); (M.S.); (A.D.); (T.K.); (I.K.); (A.T.); (L.P.); (S.S.); (A.B.B.)
| | - Leonardo Patrlj
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (M.K.); (S.G.); (I.K.); (H.Z.); (D.M.); (B.V.); (H.V.); (T.K.); (I.B.); (D.D.); (M.S.); (A.D.); (T.K.); (I.K.); (A.T.); (L.P.); (S.S.); (A.B.B.)
| | - Sanja Strbe
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (M.K.); (S.G.); (I.K.); (H.Z.); (D.M.); (B.V.); (H.V.); (T.K.); (I.B.); (D.D.); (M.S.); (A.D.); (T.K.); (I.K.); (A.T.); (L.P.); (S.S.); (A.B.B.)
| | - Antonio Kokot
- Department of Anatomy and Neuroscience, School of Medicine, Josip Juraj Strossmayer University of Osijek, 31000 Osijek, Croatia;
| | - Alenka Boban Blagaic
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (M.K.); (S.G.); (I.K.); (H.Z.); (D.M.); (B.V.); (H.V.); (T.K.); (I.B.); (D.D.); (M.S.); (A.D.); (T.K.); (I.K.); (A.T.); (L.P.); (S.S.); (A.B.B.)
| | - Anita Skrtic
- Department of Pathology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (K.H.P.); (E.L.); (M.M.); (S.S.); (A.S.); (S.S.)
| | - Sven Seiwerth
- Department of Pathology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (K.H.P.); (E.L.); (M.M.); (S.S.); (A.S.); (S.S.)
| | - Predrag Sikiric
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (M.K.); (S.G.); (I.K.); (H.Z.); (D.M.); (B.V.); (H.V.); (T.K.); (I.B.); (D.D.); (M.S.); (A.D.); (T.K.); (I.K.); (A.T.); (L.P.); (S.S.); (A.B.B.)
- Correspondence: ; Tel.: +385-1-4566-833; Fax: +385-1-492-0050
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Wu H, Wei M, Li N, Lu Q, Shrestha SM, Tan J, Zhang Z, Wu G, Shi R. Clopidogrel-Induced Gastric Injury in Rats is Attenuated by Stable Gastric Pentadecapeptide BPC 157. DRUG DESIGN DEVELOPMENT AND THERAPY 2020; 14:5599-5610. [PMID: 33376304 PMCID: PMC7763470 DOI: 10.2147/dddt.s284163] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/27/2020] [Accepted: 11/18/2020] [Indexed: 12/12/2022]
Abstract
Aim Although Clopidogrel is safe in healthy volunteers, it can induce recurrence of gastric ulcers in high-risk patients. Here, we investigated the protective effect of the natural product, stable gastric pentadecapeptide 157 (BPC 157) on Clopidogrel-induced gastric injury. Methods We used acetic acid to induce gastric ulcer in Sprague Dawley rats. Clopidogrel alone or in combination with BPC 157 or L-NAME (nitric oxide system blockade) were administered after healing of acetic acid-induced ulcer. One percent methylcellulose solution was used as control. Ulcer recurrence rate and the ulcer index were compared between these groups. Gastric mucosal apoptosis rate, microscopic inflammation activity and angiogenesis markers vascular endothelial growth factor A (VEGF-A) and CD34 were examined by TUNEL, histological evaluations (HE) and immunohistochemistry (IHC). Pathways involved, expressions of endoplasmic reticulum (ER) stress apoptosis marker CHOP, angiogenic markers VEGF-A and its receptor VEGFR1, and endothelial NO synthase (eNOS) were all analyzed by Western blot. Results This study indicated that Clopidogrel significantly induced the gastric ulcers recurrence, severe inflammation and ER stress related apoptosis of the gastric mucosa, suppressed the synthesis of angiogenic markers and eNOS. Furthermore, Clopidrogel intervention resulted in the activation of protein kinase B (AKT) and p38 mitogen-activated protein kinase (p38/MAPK). BPC 157 attenuated the gastric mucosal damage caused by Clopidogrel and reversed these molecular effects. However, NO blockade L-NAME weakened the protective effect and thus the molecular effects of BPC 157 on gastric mucosa. Conclusion In conclusion, these results suggest that BPC 157 inhibited Clopidogrel-induced gastric mucosa injury partially by inhibition of gastric mucosa cell ER stress-mediated apoptosis and inflammation, and promoting gastric mucosa angiogenesis via VEGF-A/VEGFR1 mediated-AKT/p38/MAPK signaling pathways.
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Affiliation(s)
- Hailu Wu
- Medical School of Southeast University, Nanjing 210009, People's Republic of China.,Department of Gastroenterology, Zhongda Hospital Affiliated to Southeast University, Nanjing 210009, People's Republic of China
| | - Ming Wei
- Department of Gastroenterology, Zhongda Hospital Affiliated to Southeast University, Nanjing 210009, People's Republic of China
| | - Nan Li
- Department of Gastroenterology, Zhongda Hospital Affiliated to Southeast University, Nanjing 210009, People's Republic of China
| | - Qin Lu
- Department of Gastroenterology, Zhongda Hospital Affiliated to Southeast University, Nanjing 210009, People's Republic of China
| | | | - Jiacheng Tan
- Department of Gastroenterology, Zhongda Hospital Affiliated to Southeast University, Nanjing 210009, People's Republic of China
| | - Zhenyu Zhang
- Division of Gastroenterology, Department of Medicine, Nanjing Medical University Nanjing First Hospital, Nanjing 210009, People's Republic of China
| | - Guoqiu Wu
- Center of Clinical Laboratory Medicine, Zhongda Hospital, Southeast University, Nanjing 210009, People's Republic of China.,Jiangsu Provincial Key Laboratory of Critical Care Medicine, Nanjing 210009, People's Republic of China
| | - Ruihua Shi
- Department of Gastroenterology, Zhongda Hospital Affiliated to Southeast University, Nanjing 210009, People's Republic of China
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Fedorov VN, Koroleva SV, Zubova TA, Andreeva LA, Myasoedov NF. Preparations Based on Regulatory Peptides—a New Class of Medicines. NEUROCHEM J+ 2020. [DOI: 10.1134/s1819712420040121] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
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15
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Cesar LB, Gojkovic S, Krezic I, Malekinusic D, Zizek H, Vuletic LB, Petrovic A, Pavlov KH, Drmic D, Kokot A, Vlainic J, Seiwerth S, Sikiric P. Bowel adhesion and therapy with the stable gastric pentadecapeptide BPC 157, L-NAME and L-arginine in rats. World J Gastrointest Pharmacol Ther 2020; 11:93-109. [PMID: 33251034 PMCID: PMC7667405 DOI: 10.4292/wjgpt.v11.i5.93] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/13/2020] [Revised: 08/13/2020] [Accepted: 09/10/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND After parietal peritoneum excision with an underlying superficial layer of muscle tissue in rats, there is failed vasculature, and finally, increased adhesion formation. We hypothesized that unlike nitric oxide (NO)-agents, L-NAME and/or L-arginine, the application of the stable gastric pentadecapeptide BPC 157 with its most recent vascular effects (“vascular recruitment”) means attenuated bowel adhesion formation and NO- and malondialdehyde (MDA)-tissue values.
AIM To focused on the bowel adhesion and the therapy with the BPC 157, its most and application of NO-agents.
METHODS Along with defect creation, medication was (1) during surgery, once, at 1 min after defect creation as an abdominal bath (1 mL/rat), BPC 157 (10 µg/kg, 10 ng/kg, 1 mL/rat), an equivolume of saline, L-NAME (5 mg/kg), L-arginine (200 mg/kg) alone and/or combined. Alternatively, medication was (2) intraperitoneally once daily, first application at 30 min after surgery, last application 24 h before assessment at d 7 or d 14. As a postponed therapy to pre-existing adhesion (3), BPC 157 (10 µg/kg, 10 ng/kg intraperitoneally, 1 mL/rat) was given once daily since d 7.
RESULTS The recovery effect of the BPC 157 regimens goes with the presence of abundant vascular vessels in and near the defect, which occurs rapidly. Lastly, also applied as post-treatment, BPC 157 creates attenuated adhesions, minimal or no adhesion. Contrarily, NO-agents have diverse initial and final effects: The initial weakening of blood vessel disappearance and finally, severe worsening of adhesions (L-NAME) vs the initial weakening of blood vessel disappearance and finally, attenuation of adhesions formation (L-arginine), which counteract each other response given together. Importantly, BPC 157 maintains its beneficial effect also when given with NO-agents (L-NAME + BC 157; L-arginine + BPC 157; L-NAME + L-arginine + BPC 157). Finally, with respect to the increased NO- and MDA- values-adhesion tissue formation relation, unlike diverse effect of the NO-agents, the BPC 157 application effect regularly combines decrease on the increased NO- and MDA- values and the beneficial outcome (less adhesion formation).
CONCLUSION BPC 157 therapy can be suited for the realization of the peritoneal defect healing with minimal or no adhesion formation.
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Affiliation(s)
- Lidija Berkopic Cesar
- Department of Pharmacology, School of Medicine, University of Zagreb, Zagreb 10 000, Croatia
| | - Slaven Gojkovic
- Department of Pharmacology, School of Medicine, University of Zagreb, Zagreb 10 000, Croatia
| | - Ivan Krezic
- Department of Pharmacology, School of Medicine, University of Zagreb, Zagreb 10 000, Croatia
| | - Dominik Malekinusic
- Department of Pharmacology, School of Medicine, University of Zagreb, Zagreb 10 000, Croatia
| | - Helena Zizek
- Department of Pharmacology, School of Medicine, University of Zagreb, Zagreb 10 000, Croatia
| | | | - Andreja Petrovic
- Department of Pathology, School of Medicine, University of Zagreb, Zagreb 10000, Croatia
| | - Katarina Horvat Pavlov
- Department of Pathology, School of Medicine, University of Zagreb, Zagreb 10000, Croatia
| | | | - Antonio Kokot
- Department of Pharmacology, School of Medicine, University of Zagreb, Zagreb 10 000, Croatia
| | | | - Sven Seiwerth
- Department of Pathology, School of Medicine, University of Zagreb, Zagreb 10000, Croatia
| | - Predrag Sikiric
- Department of Pharmacology, School of Medicine, University of Zagreb, Zagreb 10 000, Croatia
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Zemba Cilic A, Zemba M, Cilic M, Balenovic I, Strbe S, Ilic S, Vukojevic J, Zoricic Z, Filipcic I, Kokot A, Drmic D, Blagaic AB, Tvrdeic A, Seiwerth S, Sikiric P. Pentadecapeptide BPC 157 counteracts L-NAME-induced catalepsy. BPC 157, L-NAME, L-arginine, NO-relation, in the suited rat acute and chronic models resembling 'positive-like' symptoms of schizophrenia. Behav Brain Res 2020; 396:112919. [PMID: 32956773 DOI: 10.1016/j.bbr.2020.112919] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2019] [Revised: 08/15/2020] [Accepted: 09/14/2020] [Indexed: 12/13/2022]
Abstract
In the suited rat-models, we focused on the stable pentadecapeptide BPC 157, L-NAME, NOS-inhibitor, and L-arginine, NOS-substrate, relation, the effect on schizophrenia-like symptoms. Medication (mg/kg intraperitoneally) was L-NAME (5), L-arginine (100), BPC 157 (0.01), given alone and/or together, at 5 min before the challenge for the acutely disturbed motor activity (dopamine-indirect/direct agonists (amphetamine (3.0), apomorphine (2.5)), NMDA-receptor non-competitive antagonist (MK-801 (0.2)), or catalepsy, (dopamine-receptor antagonist haloperidol (2.0)). Alternatively, BPC 157 10 μg/kg was given immediately after L-NAME 40 mg/kg intraperitoneally. To induce or prevent sensitization, we used chronic methamphetamine administration, alternating 3 days during the first 3 weeks, and challenge after next 4 weeks, and described medication (L-NAME, L-arginine, BPC 157) at 5 min before the methamphetamine at the second and third week. Given alone, BPC 157 or L-arginine counteracted the amphetamine-, apomorphine-, and MK-801-induced effect, haloperidol-induced catalepsy and chronic methamphetamine-induced sensitization. L-NAME did not affect the apomorphine-, and MK-801-induced effects, haloperidol-induced catalepsy and chronic methamphetamine-induced sensitization, but counteracted the acute amphetamine-induced effect. In combinations (L-NAME + L-arginine), as NO-specific counteraction, L-NAME counteracts L-arginine-induced counteractions in the apomorphine-, MK-801-, haloperidol- and methamphetamine-rats, but not in amphetamine-rats. Unlike L-arginine, BPC 157 maintains its counteracting effect in the presence of the NOS-blockade (L-NAME + BPC 157) or NO-system-over-stimulation (L-arginine + BPC 157). Illustrating the BPC 157-L-arginine relationships, BPC 157 restored the antagonization (L-NAME + L-arginine + BPC 157) when it had been abolished by the co-administration of L-NAME with L-arginine (L-NAME + L-arginine). Finally, BPC 157 directly inhibits the L-NAME high dose-induced catalepsy. Further studies would determine precise BPC 157/dopamine/glutamate/NO-system relationships and clinical application.
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Affiliation(s)
- Andrea Zemba Cilic
- Departments of Pharmacology and Pathology, School of Medicine, University of Zagreb, Zagreb, Croatia
| | - Mladen Zemba
- Departments of Pharmacology and Pathology, School of Medicine, University of Zagreb, Zagreb, Croatia
| | - Matija Cilic
- Departments of Pharmacology and Pathology, School of Medicine, University of Zagreb, Zagreb, Croatia
| | - Igor Balenovic
- Departments of Pharmacology and Pathology, School of Medicine, University of Zagreb, Zagreb, Croatia
| | - Sanja Strbe
- Departments of Pharmacology and Pathology, School of Medicine, University of Zagreb, Zagreb, Croatia
| | - Spomenko Ilic
- Departments of Pharmacology and Pathology, School of Medicine, University of Zagreb, Zagreb, Croatia
| | - Jaksa Vukojevic
- Departments of Pharmacology and Pathology, School of Medicine, University of Zagreb, Zagreb, Croatia
| | - Zoran Zoricic
- Departments of Pharmacology and Pathology, School of Medicine, University of Zagreb, Zagreb, Croatia
| | - Igor Filipcic
- Departments of Pharmacology and Pathology, School of Medicine, University of Zagreb, Zagreb, Croatia
| | - Antonio Kokot
- Departments of Pharmacology and Pathology, School of Medicine, University of Zagreb, Zagreb, Croatia
| | - Domagoj Drmic
- Departments of Pharmacology and Pathology, School of Medicine, University of Zagreb, Zagreb, Croatia
| | - Alenka Boban Blagaic
- Departments of Pharmacology and Pathology, School of Medicine, University of Zagreb, Zagreb, Croatia
| | - Ante Tvrdeic
- Departments of Pharmacology and Pathology, School of Medicine, University of Zagreb, Zagreb, Croatia
| | - Sven Seiwerth
- Departments of Pharmacology and Pathology, School of Medicine, University of Zagreb, Zagreb, Croatia
| | - Predrag Sikiric
- Departments of Pharmacology and Pathology, School of Medicine, University of Zagreb, Zagreb, Croatia.
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Mirković I, Kralj T, Lozić M, Stambolija V, Kovačević J, Vrdoljak L, Zlatar M, Milanović K, Drmić D, Predović J, Masnec S, Jurjević M, Bušić M, Seiwerth S, Kokot A, Sikirić P. Pentadecapeptide BPC 157 shortens duration of tetracaine- and oxybuprocaine-induced corneal anesthesia in rats. Acta Clin Croat 2020; 59:394-406. [PMID: 34177048 PMCID: PMC8212645 DOI: 10.20471/acc.2020.59.03.02] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
We focused on the relationship of 0.5% tetracaine- and 0.4% oxybuprocaine-induced corneal anesthesia in rats, and pentadecapeptide BPC 157 (0.4 µg/eye), along with nitric oxide synthase (NOS) inhibitor N(gamma)-nitro-L-arginine methyl ester (L-NAME) (0.1 mg/eye) and/or NOS substrate L-arginine (2 mg/eye), applied in the form of eye drops. We assessed corneal sensitivity recovery (Cochet-Bonnet esthesiometer), corneal lesion elimination (staining with 10% fluorescein) and decrease in tear volume (Schirmer test). BPC 157 administration had a full counteracting effect. Recovery also occurred in the presence of NOS blockade and NOS substrate application. L-arginine eventually shortened duration of corneal insensitivity and exerted corneal lesion counteraction (and counteraction of tetracaine-induced decrease of tear volume) only in earlier but not in later period. L-NAME application led to longer duration of corneal insensitivity, increase in corneal lesions and decrease in tear volume. When L-NAME and L-arginine were applied together, they antagonized each other’s effect. These distinctions may indicate particular NOS involvement (corneal insensitivity vs. corneal lesion along with tear production), distinctively affected by the administration of NO agents. However, additional BPC 157 co-administration would re-establish counteraction over topical ophthalmic anesthetic-induced effect, be it in its early or late course. We suggest BPC 157 as an antidote to topical ophthalmic anesthetics.
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Affiliation(s)
| | - Tamara Kralj
- 1Department of Pharmacology, School of Medicine, University of Zagreb, Zagreb, Croatia; 2Department of Anatomy and Neuroscience, Osijek Faculty of Medicine, Josip Juraj Strossmayer University of Osijek, Osijek, Croatia; 3Department of Ophthalmology, Sveti Duh University Hospital, Zagreb, Croatia; 4Department of Ophthalmology, Zagreb University Hospital Centre, Zagreb, Croatia
| | - Marin Lozić
- 1Department of Pharmacology, School of Medicine, University of Zagreb, Zagreb, Croatia; 2Department of Anatomy and Neuroscience, Osijek Faculty of Medicine, Josip Juraj Strossmayer University of Osijek, Osijek, Croatia; 3Department of Ophthalmology, Sveti Duh University Hospital, Zagreb, Croatia; 4Department of Ophthalmology, Zagreb University Hospital Centre, Zagreb, Croatia
| | - Vasilije Stambolija
- 1Department of Pharmacology, School of Medicine, University of Zagreb, Zagreb, Croatia; 2Department of Anatomy and Neuroscience, Osijek Faculty of Medicine, Josip Juraj Strossmayer University of Osijek, Osijek, Croatia; 3Department of Ophthalmology, Sveti Duh University Hospital, Zagreb, Croatia; 4Department of Ophthalmology, Zagreb University Hospital Centre, Zagreb, Croatia
| | - Josip Kovačević
- 1Department of Pharmacology, School of Medicine, University of Zagreb, Zagreb, Croatia; 2Department of Anatomy and Neuroscience, Osijek Faculty of Medicine, Josip Juraj Strossmayer University of Osijek, Osijek, Croatia; 3Department of Ophthalmology, Sveti Duh University Hospital, Zagreb, Croatia; 4Department of Ophthalmology, Zagreb University Hospital Centre, Zagreb, Croatia
| | - Luka Vrdoljak
- 1Department of Pharmacology, School of Medicine, University of Zagreb, Zagreb, Croatia; 2Department of Anatomy and Neuroscience, Osijek Faculty of Medicine, Josip Juraj Strossmayer University of Osijek, Osijek, Croatia; 3Department of Ophthalmology, Sveti Duh University Hospital, Zagreb, Croatia; 4Department of Ophthalmology, Zagreb University Hospital Centre, Zagreb, Croatia
| | - Mirna Zlatar
- 1Department of Pharmacology, School of Medicine, University of Zagreb, Zagreb, Croatia; 2Department of Anatomy and Neuroscience, Osijek Faculty of Medicine, Josip Juraj Strossmayer University of Osijek, Osijek, Croatia; 3Department of Ophthalmology, Sveti Duh University Hospital, Zagreb, Croatia; 4Department of Ophthalmology, Zagreb University Hospital Centre, Zagreb, Croatia
| | - Kristina Milanović
- 1Department of Pharmacology, School of Medicine, University of Zagreb, Zagreb, Croatia; 2Department of Anatomy and Neuroscience, Osijek Faculty of Medicine, Josip Juraj Strossmayer University of Osijek, Osijek, Croatia; 3Department of Ophthalmology, Sveti Duh University Hospital, Zagreb, Croatia; 4Department of Ophthalmology, Zagreb University Hospital Centre, Zagreb, Croatia
| | - Domagoj Drmić
- 1Department of Pharmacology, School of Medicine, University of Zagreb, Zagreb, Croatia; 2Department of Anatomy and Neuroscience, Osijek Faculty of Medicine, Josip Juraj Strossmayer University of Osijek, Osijek, Croatia; 3Department of Ophthalmology, Sveti Duh University Hospital, Zagreb, Croatia; 4Department of Ophthalmology, Zagreb University Hospital Centre, Zagreb, Croatia
| | - Jurica Predović
- 1Department of Pharmacology, School of Medicine, University of Zagreb, Zagreb, Croatia; 2Department of Anatomy and Neuroscience, Osijek Faculty of Medicine, Josip Juraj Strossmayer University of Osijek, Osijek, Croatia; 3Department of Ophthalmology, Sveti Duh University Hospital, Zagreb, Croatia; 4Department of Ophthalmology, Zagreb University Hospital Centre, Zagreb, Croatia
| | - Sanja Masnec
- 1Department of Pharmacology, School of Medicine, University of Zagreb, Zagreb, Croatia; 2Department of Anatomy and Neuroscience, Osijek Faculty of Medicine, Josip Juraj Strossmayer University of Osijek, Osijek, Croatia; 3Department of Ophthalmology, Sveti Duh University Hospital, Zagreb, Croatia; 4Department of Ophthalmology, Zagreb University Hospital Centre, Zagreb, Croatia
| | - Matija Jurjević
- 1Department of Pharmacology, School of Medicine, University of Zagreb, Zagreb, Croatia; 2Department of Anatomy and Neuroscience, Osijek Faculty of Medicine, Josip Juraj Strossmayer University of Osijek, Osijek, Croatia; 3Department of Ophthalmology, Sveti Duh University Hospital, Zagreb, Croatia; 4Department of Ophthalmology, Zagreb University Hospital Centre, Zagreb, Croatia
| | - Mladen Bušić
- 1Department of Pharmacology, School of Medicine, University of Zagreb, Zagreb, Croatia; 2Department of Anatomy and Neuroscience, Osijek Faculty of Medicine, Josip Juraj Strossmayer University of Osijek, Osijek, Croatia; 3Department of Ophthalmology, Sveti Duh University Hospital, Zagreb, Croatia; 4Department of Ophthalmology, Zagreb University Hospital Centre, Zagreb, Croatia
| | - Sven Seiwerth
- 1Department of Pharmacology, School of Medicine, University of Zagreb, Zagreb, Croatia; 2Department of Anatomy and Neuroscience, Osijek Faculty of Medicine, Josip Juraj Strossmayer University of Osijek, Osijek, Croatia; 3Department of Ophthalmology, Sveti Duh University Hospital, Zagreb, Croatia; 4Department of Ophthalmology, Zagreb University Hospital Centre, Zagreb, Croatia
| | - Antonio Kokot
- 1Department of Pharmacology, School of Medicine, University of Zagreb, Zagreb, Croatia; 2Department of Anatomy and Neuroscience, Osijek Faculty of Medicine, Josip Juraj Strossmayer University of Osijek, Osijek, Croatia; 3Department of Ophthalmology, Sveti Duh University Hospital, Zagreb, Croatia; 4Department of Ophthalmology, Zagreb University Hospital Centre, Zagreb, Croatia
| | - Predrag Sikirić
- 1Department of Pharmacology, School of Medicine, University of Zagreb, Zagreb, Croatia; 2Department of Anatomy and Neuroscience, Osijek Faculty of Medicine, Josip Juraj Strossmayer University of Osijek, Osijek, Croatia; 3Department of Ophthalmology, Sveti Duh University Hospital, Zagreb, Croatia; 4Department of Ophthalmology, Zagreb University Hospital Centre, Zagreb, Croatia
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Vukojević J, Vrdoljak B, Malekinušić D, Siroglavić M, Milavić M, Kolenc D, Boban Blagaić A, Batelja L, Drmić D, Seiverth S, Sikirić P. The effect of pentadecapeptide BPC 157 on hippocampal ischemia/reperfusion injuries in rats. Brain Behav 2020; 10:e01726. [PMID: 32558293 PMCID: PMC7428500 DOI: 10.1002/brb3.1726] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/29/2019] [Revised: 05/27/2020] [Accepted: 05/28/2020] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND AND PURPOSE We focused on the, yet undescribed, therapy effect of the stable gastric pentadecapeptide BPC 157 in hippocampal ischemia/reperfusion injuries, after bilateral clamping of the common carotid arteries in rats. The background is the proven therapy effect of BPC 157 in ischemia/reperfusion injuries in different tissues. Furthermore, there is the subsequent oxidative stress counteraction, particularly when given during reperfusion. The recovering effect it has on occluded vessels, results with activation of the alternative pathways, bypassing the occlusion in deep vein thrombosis. Finally, the BPC 157 therapy benefits with its proposed role as a novel mediator of Roberts' cytoprotection and bidirectional effects in the gut-brain axis. MATERIALS AND METHODS Male Wistar rats underwent bilateral clamping of the common carotid arteries for a 20-min period. At 30 s thereafter, we applied medication (BPC 157 10 µg/kg; or saline) as a 1 ml bath directly to the operated area, that is, trigonum caroticum. We documented, in reperfusion, the resolution of the neuronal damages sustained in the brain, resolution of the damages reflected in memory, locomotion, and coordination disturbances, with the presentation of the particular genes expression in hippocampal tissues. RESULTS In the operated rats, at 24 and 72 hr of the reperfusion, the therapy counteracted both early and delayed neural hippocampal damage, achieving full functional recovery (Morris water maze test, inclined beam-walking test, lateral push test). mRNA expression studies at 1 and 24 hr, provided strongly elevated (Egr1, Akt1, Kras, Src, Foxo, Srf, Vegfr2, Nos3, and Nos1) and decreased (Nos2, Nfkb) gene expression (Mapk1 not activated), as a way how BPC 157 may act. CONCLUSION Together, these findings suggest that these beneficial BPC 157 effects may provide a novel therapeutic solution for stroke.
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Affiliation(s)
- Jakša Vukojević
- Department of Pharmacology, Medical School, University of Zagreb, Zagreb, Croatia
| | - Borna Vrdoljak
- Department of Pharmacology, Medical School, University of Zagreb, Zagreb, Croatia
| | - Dominik Malekinušić
- Department of Pharmacology, Medical School, University of Zagreb, Zagreb, Croatia
| | - Marko Siroglavić
- Department of Pharmacology, Medical School, University of Zagreb, Zagreb, Croatia
| | - Marija Milavić
- Department of Pathology, Medical School, University of Zagreb, Zagreb, Croatia
| | - Danijela Kolenc
- Department of Pathology, Medical School, University of Zagreb, Zagreb, Croatia
| | - Alenka Boban Blagaić
- Department of Pharmacology, Medical School, University of Zagreb, Zagreb, Croatia
| | - Lovorka Batelja
- Department of Pathology, Medical School, University of Zagreb, Zagreb, Croatia
| | - Domagoj Drmić
- Department of Pharmacology, Medical School, University of Zagreb, Zagreb, Croatia
| | - Sven Seiverth
- Department of Pathology, Medical School, University of Zagreb, Zagreb, Croatia
| | - Predrag Sikirić
- Department of Pharmacology, Medical School, University of Zagreb, Zagreb, Croatia
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In relation to NO-System, Stable Pentadecapeptide BPC 157 Counteracts Lidocaine-Induced Adverse Effects in Rats and Depolarisation In Vitro. Emerg Med Int 2020; 2020:6805354. [PMID: 32566305 PMCID: PMC7273470 DOI: 10.1155/2020/6805354] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2020] [Revised: 04/28/2020] [Accepted: 04/30/2020] [Indexed: 02/07/2023] Open
Abstract
Recently, the pentadecapeptide BPC 157-induced counteraction of bupivacaine cardiotoxicity has been reported. Medication includes (i) lidocaine-induced local anesthesia via intraplantar application and axillary and spinal (L4-L5) intrathecal block, (ii) lidocaine-induced arrhythmias, (iii) convulsions, and (iv) lidocaine-induced HEK293 cell depolarisation. BPC 157 applications (intraplantar, intraperitoneal, and intragastric) were given (i) immediately after lidocaine, (ii) 10 min after, or (iii) 5 min before. The BPC 157/NO-system relationship was verified with NO-agents, the NOS-blocker L-NAME and the NOS-substrate L-arginine, given alone and/or together, in axillary and spinal intrathecal blocks. BPC 157 applied immediately after lidocaine or 5 min before the application of lidocaine considerably ameliorated plantar presentation. BPC 157 medication considerably counteracted lidocaine-induced limb function failure; L-NAME was counteracted; L-arginine exhibited counteraction when given immediately after lidocaine, but prolongation was seen when given later. Given together, prophylactically or therapeutically, L-NAME and L-arginine (L-NAME + L-arginine) counteracted the other's response. BPC 157 maintained its original response when given together with L-NAME or L-arginine. When BPC 157 was given together with L-NAME and L-arginine, its original response reappeared. BPC 157 antagonised the lidocaine-induced bradycardia and eliminated tonic-clonic convulsions. Also, BPC 157 counteracted the lidocaine-induced depolarisation of HEK293 cells. Thus, BPC 157 has antidote activity in its own right against lidocaine and local anesthetics.
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Xu C, Sun L, Ren F, Huang P, Tian Z, Cui J, Zhang W, Wang S, Zhang K, He L, Zhang W, Zhang C, Hao Q, Zhang Y, Li M, Li W. Preclinical safety evaluation of body protective compound-157, a potential drug for treating various wounds. Regul Toxicol Pharmacol 2020; 114:104665. [PMID: 32334036 DOI: 10.1016/j.yrtph.2020.104665] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2019] [Revised: 03/09/2020] [Accepted: 04/17/2020] [Indexed: 12/22/2022]
Abstract
BPC157 displays protective activity in various organs and tissues. This report presents preclinical toxicity studies with BPC157 in mice, rats, rabbits and dogs. The single-dose toxicity study did not show any test-related effects that could be attributed to the test article. In repeated-dose toxicity evaluations, BPC157 was well tolerated in dogs, with no abnormal changes between the BPC157-treated groups and the solvent control group, with the exception of a decrease in creatinine level at a dose of 2 mg/kg but not at lower doses. The animals recovered spontaneously after 2 weeks of withdrawal. This may be due to the pharmacological activity of BPC157. A local tolerance test showed that the irritation caused by BPC157 was mild. BPC157 also showed no genetic or embryo-fetal toxicity. In summary, BPC157 was well tolerated and did not cause any serious toxicity in mice, rats, rabbits and dogs. These preclinical safety data contribute to the initiation of an ongoing clinical study. Based on the stability and protective effect of BPC157, which has been widely reported, BPC157 may have a better application prospect than the widely used cytokine drugs in wound therapy.
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Affiliation(s)
- Chuanyang Xu
- State Key Laboratory of Cancer Biology, Biotechnology Center, School of Pharmacy, Fourth Military Medical University, Xi'an, 710032, China
| | - Lijuan Sun
- Department of Ophthalmology, Eye Institute of Chinese PLA, Xijing Hospital, Fourth Military Medical University, Xi'an, 710032, China
| | - FengLing Ren
- School of Public Health, Health Science Center, Xi'an Jiaotong University, Xi'an, 710061, China
| | - Ping Huang
- The Brigade of Undergraduates, The Fourth Military Medical University, Xi'an, 710032, China
| | - Zhuang Tian
- The Brigade of Undergraduates, The Fourth Military Medical University, Xi'an, 710032, China
| | - Jiazhen Cui
- The Brigade of Undergraduates, The Fourth Military Medical University, Xi'an, 710032, China
| | - Wangqian Zhang
- State Key Laboratory of Cancer Biology, Biotechnology Center, School of Pharmacy, Fourth Military Medical University, Xi'an, 710032, China
| | - Shuning Wang
- State Key Laboratory of Cancer Biology, Biotechnology Center, School of Pharmacy, Fourth Military Medical University, Xi'an, 710032, China
| | - Kuo Zhang
- State Key Laboratory of Cancer Biology, Biotechnology Center, School of Pharmacy, Fourth Military Medical University, Xi'an, 710032, China
| | - Lei He
- State Key Laboratory of Cancer Biology, Biotechnology Center, School of Pharmacy, Fourth Military Medical University, Xi'an, 710032, China
| | - Wei Zhang
- State Key Laboratory of Cancer Biology, Biotechnology Center, School of Pharmacy, Fourth Military Medical University, Xi'an, 710032, China
| | - Cun Zhang
- State Key Laboratory of Cancer Biology, Biotechnology Center, School of Pharmacy, Fourth Military Medical University, Xi'an, 710032, China
| | - Qiang Hao
- State Key Laboratory of Cancer Biology, Biotechnology Center, School of Pharmacy, Fourth Military Medical University, Xi'an, 710032, China
| | - Yingqi Zhang
- State Key Laboratory of Cancer Biology, Biotechnology Center, School of Pharmacy, Fourth Military Medical University, Xi'an, 710032, China
| | - Meng Li
- State Key Laboratory of Cancer Biology, Biotechnology Center, School of Pharmacy, Fourth Military Medical University, Xi'an, 710032, China.
| | - Weina Li
- State Key Laboratory of Cancer Biology, Biotechnology Center, School of Pharmacy, Fourth Military Medical University, Xi'an, 710032, China.
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Sikiric P, Hahm KB, Blagaic AB, Tvrdeic A, Pavlov KH, Petrovic A, Kokot A, Gojkovic S, Krezic I, Drmic D, Rucman, R, Seiwerth S. Stable Gastric Pentadecapeptide BPC 157, Robert's Stomach Cytoprotection/Adaptive Cytoprotection/Organoprotection, and Selye's Stress Coping Response: Progress, Achievements, and the Future. Gut Liver 2020; 14:153-167. [PMID: 31158953 PMCID: PMC7096228 DOI: 10.5009/gnl18490] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/05/2018] [Revised: 01/10/2019] [Accepted: 01/21/2019] [Indexed: 12/14/2022] Open
Abstract
We reviewed again the significance of the stable gastric pentadecapeptide BPC 157 as a likely mediator of Robert's stomach cytoprotection/adaptive cytoprotection and organoprotection and as novel mediator of Selye's stress coping response to reestablish homeostasis. Specific points of BPC 157 therapy and the original concept of Robert's cytoprotection/adaptive cytoprotection/organoprotection are discussed, including the beneficial effects of BPC 157. First, BPC 157 protects stomach cells and maintains gastric integrity against various noxious agents (Robert's killing cell by contact) and is continuously present in the gastric mucosa and gastric juice. Additionally, BPC 157 protects against the adverse effects of alcohol and nonsteroidal anti-inflammatory drugs on the gastric epithelium and other epithelia, that is, skin, liver, pancreas, heart (organoprotection), and brain, thereby suggesting its use in wound healing. Additionally, BPC 157 counteracts gastric endothelial injury that precedes and induces damage to the gastric epithelium and generalizes "gastric endothelial protection" to protection of the endothelium of other vessels (thrombosis, prolonged bleeding, and thrombocytopenia). BPC 157 also has an effect on blood vessels, resulting in vessel recruitment that circumvents vessel occlusion and the development of additional shunting and rapid bypass loops to rapidly reestablish the integrity of blood flow (ischemic/reperfusion colitis, duodenal lesions, cecal perforation, and inferior vena caval occlusion). Lastly, BPC 157 counteracts tumor cachexia, muscle wasting, and increases in pro-inflammatory/procachectic cytokines, such as interleukin-6 and tumor necrosis factor-α, and significantly corrects deranged muscle proliferation and myogenesis through changes in the expression of FoxO3a, p-AKT, p-mTOR, and p-GSK-3β (mitigating cancer cachexia).
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Affiliation(s)
- Predrag Sikiric
- Department of Pharmacology, Medical Faculty, University of Zagreb, Zagreb, Croatia
| | - Ki-Baik Hahm
- Digestive Disease Center, CHA Bundang Medical Center, CHA University School of Medicine, Seongnam, Korea
| | - Alenka Boban Blagaic
- Department of Pharmacology, Medical Faculty, University of Zagreb, Zagreb, Croatia
| | - Ante Tvrdeic
- Department of Pharmacology, Medical Faculty, University of Zagreb, Zagreb, Croatia
| | | | - Andrea Petrovic
- Department of Pathology, Medical Faculty, University of Zagreb, Zagreb, Croatia
| | - Antonio Kokot
- Department of Pharmacology, Medical Faculty, University of Zagreb, Zagreb, Croatia
| | - Slaven Gojkovic
- Department of Pharmacology, Medical Faculty, University of Zagreb, Zagreb, Croatia
| | - Ivan Krezic
- Department of Pharmacology, Medical Faculty, University of Zagreb, Zagreb, Croatia
| | - Domagoj Drmic
- Department of Pharmacology, Medical Faculty, University of Zagreb, Zagreb, Croatia
| | - Rudolf Rucman,
- Department of Pharmacology, Medical Faculty, University of Zagreb, Zagreb, Croatia
| | - Sven Seiwerth
- Department of Pathology, Medical Faculty, University of Zagreb, Zagreb, Croatia
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22
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Gojkovic S, Krezic I, Vrdoljak B, Malekinusic D, Barisic I, Petrovic A, Horvat Pavlov K, Kolovrat M, Duzel A, Knezevic M, Kasnik Kovac K, Drmic D, Batelja Vuletic L, Kokot A, Boban Blagaic A, Seiwerth S, Sikiric P. Pentadecapeptide BPC 157 resolves suprahepatic occlusion of the inferior caval vein, Budd-Chiari syndrome model in rats. World J Gastrointest Pathophysiol 2020; 11:1-19. [PMID: 32226643 PMCID: PMC7093306 DOI: 10.4291/wjgp.v11.i1.1] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/07/2019] [Revised: 12/20/2019] [Accepted: 02/11/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Recently, as a possible therapy resolving solution, pentadecapeptide BPC 157 therapy, has been used in alleviating various vascular occlusion disturbances. BPC 157 was previously reviewed as novel mediator of Robert cytoprotection and endothelium protection in the stomach, and gut-brain axis, beneficial therapy in gastrointestinal tract, with particular reference to vascular recruitment, ulcerative colitis and tumor cachexia, and other tissues healing. Here we raised new hypothesis about BPC 157 therapy in the Budd-Chiari syndrome in rats, rapid bypassing of the suprahepatic inferior caval vein occlusion, and rats recovery with the active and effective pharmacotherapy treatment.
AIM To investigate Budd-Chiari syndrome model (inferior caval vein suprahepatic occlusion) resolution, since BPC 157 resolves various rat vascular occlusion.
METHODS We assessed the activated bypassing pathways between the inferior and superior caval veins and portocaval shunt, counteracted caval/portal hypertension, aortal hypotension, venous/arterial thrombosis, electrocardiogram disturbances, liver and gastrointestinal lesions (i.e., stomach and duodenum hemorrhages, in particular, congestion). Rats with suprahepatic occlusion of the inferior vena cava by ligation were medicated at 1 min, 15 min, 24 h, or 48 h post-ligation. Medication consisted of 10 µg/kg BPC 157, 10 ng BPC 157 or 5 mL/kg saline, administered once as an abdominal bath or intragastric application. Gross and microscopic observations were made, in addition to assessments of electrical activity of the heart (electrocardiogram), portal and caval hypertension, aortal hypotension, thrombosis, hepatomegaly, splenomegaly and venography. Furthermore, levels of nitric oxide, malondialdehyde in the liver and serum enzymes were determined.
RESULTS BPC 157 counteracted increased P wave amplitude, tachycardia and ST-elevation, i.e., right heart failure from acute thrombotic coronary occlusion. The bypassing pathway of the inferior vena cava-azygos (hemiazygos) vein-superior vena cava and portocaval shunt occurred rapidly. Even with severe caval ˃ portal hypertension, BPC 157 antagonized portal and caval hypertension and aortal hypotension, and also reduced refractory ascites. Thrombosis of portal vein tributaries, inferior vena cava, and hepatic and coronary arteries was attenuated. In addition, there was reduced pathology of the lungs (severe capillary congestion) and liver (dilated central veins and terminal portal venules), decreased intestine hemorrhagic lesions (substantial capillary congestion, submucosal edema and architecture loss), and increased liver and spleen weight. During the period of ligation, nitric oxide- and malondialdehyde-levels in the liver remained within normal healthy values, and increases in serum enzymes were markedly reduced.
CONCLUSION BPC 157 counteracts Budd Chiari syndrome in rats.
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Affiliation(s)
- Slaven Gojkovic
- Departments of Pharmacology and Pathology, Medical Faculty University of Zagreb, Zagreb 10000, Croatia
| | - Ivan Krezic
- Departments of Pharmacology and Pathology, Medical Faculty University of Zagreb, Zagreb 10000, Croatia
| | - Borna Vrdoljak
- Departments of Pharmacology and Pathology, Medical Faculty University of Zagreb, Zagreb 10000, Croatia
| | - Dominik Malekinusic
- Departments of Pharmacology and Pathology, Medical Faculty University of Zagreb, Zagreb 10000, Croatia
| | - Ivan Barisic
- Departments of Pharmacology and Pathology, Medical Faculty University of Zagreb, Zagreb 10000, Croatia
| | - Andreja Petrovic
- Departments of Pharmacology and Pathology, Medical Faculty University of Zagreb, Zagreb 10000, Croatia
| | - Katarina Horvat Pavlov
- Departments of Pharmacology and Pathology, Medical Faculty University of Zagreb, Zagreb 10000, Croatia
| | - Marijan Kolovrat
- Departments of Pharmacology and Pathology, Medical Faculty University of Zagreb, Zagreb 10000, Croatia
| | - Antonija Duzel
- Departments of Pharmacology and Pathology, Medical Faculty University of Zagreb, Zagreb 10000, Croatia
| | - Mario Knezevic
- Departments of Pharmacology and Pathology, Medical Faculty University of Zagreb, Zagreb 10000, Croatia
| | - Katarina Kasnik Kovac
- Departments of Pharmacology and Pathology, Medical Faculty University of Zagreb, Zagreb 10000, Croatia
| | - Domagoj Drmic
- Departments of Pharmacology and Pathology, Medical Faculty University of Zagreb, Zagreb 10000, Croatia
| | - Lovorka Batelja Vuletic
- Departments of Pharmacology and Pathology, Medical Faculty University of Zagreb, Zagreb 10000, Croatia
| | - Antonio Kokot
- Departments of Pharmacology and Pathology, Medical Faculty University of Zagreb, Zagreb 10000, Croatia
| | - Alenka Boban Blagaic
- Departments of Pharmacology and Pathology, Medical Faculty University of Zagreb, Zagreb 10000, Croatia
| | - Sven Seiwerth
- Departments of Pharmacology and Pathology, Medical Faculty University of Zagreb, Zagreb 10000, Croatia
| | - Predrag Sikiric
- Departments of Pharmacology and Pathology, Medical Faculty University of Zagreb, Zagreb 10000, Croatia
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23
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Intragastric Application of Aspirin, Clopidogrel, Cilostazol, and BPC 157 in Rats: Platelet Aggregation and Blood Clot. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2019; 2019:9084643. [PMID: 31976029 PMCID: PMC6955135 DOI: 10.1155/2019/9084643] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/13/2019] [Revised: 09/24/2019] [Accepted: 12/11/2019] [Indexed: 02/07/2023]
Abstract
We suggest that the stable gastric pentadecapeptide BPC 157 may rescue thrombocyte function. We focused on the antithrombotic agent aspirin, clopidogrel, and cilostazol application in rats; arachidonic acid, ADP, collagen, and arachidonic acid/PGE1 platelet aggregation (aggregometry) and blood clot viscoelastic properties (thromboelastometry); and the pentadecapeptide BPC 157. Rats received intragastrically for three days once daily treatment with antithrombotic agents—aspirin (10 mg/kg) or clopidogrel (10 mg/kg) or cilostazol (10 mg/kg). Medication (BPC 157 (10 μg/kg) or an equal volume of saline (5 ml/kg)) was given intragastrically, immediately after each antithrombotic agent application. For multiple electrode aggregometry and modified rotational thromboelastometry studies, blood sampling was at 2 h after last application. Adenosine diphosphate (ADP test 6.5 μM), arachidonic acid (ASPI test 0.5 mM), a combination of arachidonic acid and prostaglandin E1 (ASPI test 0.5 mM and PGE1-test 30 nM), and collagen (COL test 3.2 μg/ml) were used as aggregation agonists. Given with aspirin, clopidogrel, or cilostazol in rats, BPC 157 counteracted their inhibitory effects on aggregation activated by arachidonic acid, ADP, collagen, and arachidonic acid/PGE1. Specifically, this includes recovery of the aggregation induced by arachidonic acid (vs. aspirin, vs. clopidogrel, and vs. cilostazol), arachidonic acid/PGE1 (vs. cilostazol), ADP (vs. clopidogrel), or collagen (vs. clopidogrel). Contrarily, there is no effect on the used tests (extrinsic/intrinsic hemostasis system, the fibrin part of the clot) EXTEM, INTEM, and FIBTEM; clotting time; clot formation time; alpha-angle; maximum clot firmness; lysis index after 30 minutes; and maximum lysis. In conclusion, we revealed that BPC 157 largely rescues thrombocyte function.
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Sucic M, Luetic K, Jandric I, Drmic D, Sever AZ, Vuletic LB, Halle ZB, Strinic D, Kokot A, Seiwerth RS, Zoricic I, Blagaic AB, Seiwerth S, Sikiric P. Therapy of the rat hemorrhagic cystitis induced by cyclophosphamide. Stable gastric pentadecapeptide BPC 157, L-arginine, L-NAME. Eur J Pharmacol 2019; 861:172593. [PMID: 31401154 DOI: 10.1016/j.ejphar.2019.172593] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2019] [Revised: 08/01/2019] [Accepted: 08/07/2019] [Indexed: 02/07/2023]
Abstract
We focused on the cyclophosphamide-induced hemorrhagic cystitis (100 mg/kg/day intraperitoneally throughout three days) as a particular NO-system disturbance, and therapy possibilities. We demonstrated that it may be attenuated by subsequent administration of the NOS substrate L-arginine (100 mg/kg/day intraperitoneally), aggravated by NOS-blocker L-NAME (5 mg/kg/day intraperitoneally), all influenced by the stable gastric pentadecapeptide BPC 157 (10 μg/kg/day, 10 ng/kg/day, intraperitoneally or perorally, in drinking water). Regularly, cyclophosphamide dose- and time-dependently induced severe hemorrhagic cystitis lesions, gross lesions, and corresponding urothelial necrosis, vesical edema, erosion, hemorrhage, inflammation, and ulceration, microscopically. The bladder wet weight dramatically increased. Functionally, already after first cyclophosphamide administration, there is an increased leak point pressure. Until the second cyclophosphamide administration, L-arginine consistently attenuated regular cyclophosphamide-induced severe hemorrhagic cystitis lesions, grossly and microscopically, but not functionally. L-NAME aggravated these lesions and eradicated beneficial effect of L-arginine when combined. BPC 157 administration after cyclophosphamide, given in either dose or in either regimen markedly attenuated all cyclophosphamide lesions, grossly, microscopically. The increase of the bladder wet weight was consistently attenuated. Functionally, increased leak point pressure was reversed to the values noted in normal rats. The similar findings were noted in rats that received BPC 157 together with L-NAME or L-arginine, given alone or combined. Thus, the lesions are NO-related based on the administration of L-NAME as well as administration of L-arginine, and their mutual interaction, and counteraction by BPC 157 application. Likewise, we reveal new therapeutic possibilities, emphasizing stable gastric pentadecapeptide BPC 157 and L-arginine, versus L-NAME in rats underwent cyclophosphamide-induced cystitis.
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Affiliation(s)
- Mario Sucic
- Department of Pharmacology, School of Medicine, University of Zagreb, POB 916, Salata 11, 10000, Zagreb, Croatia
| | - Kresimir Luetic
- Department of Pharmacology, School of Medicine, University of Zagreb, POB 916, Salata 11, 10000, Zagreb, Croatia
| | - Ivan Jandric
- Department of Pharmacology, School of Medicine, University of Zagreb, POB 916, Salata 11, 10000, Zagreb, Croatia
| | - Domagoj Drmic
- Department of Pharmacology, School of Medicine, University of Zagreb, POB 916, Salata 11, 10000, Zagreb, Croatia
| | - Anita Zenko Sever
- Department of Pathology, School of Medicine, University of Zagreb, Salata 10, 10000, Zagreb, Croatia
| | - Lovorka Batelja Vuletic
- Department of Pathology, School of Medicine, University of Zagreb, Salata 10, 10000, Zagreb, Croatia
| | - Zeljka Belosic Halle
- Department of Pharmacology, School of Medicine, University of Zagreb, POB 916, Salata 11, 10000, Zagreb, Croatia
| | - Dean Strinic
- Department of Pharmacology, School of Medicine, University of Zagreb, POB 916, Salata 11, 10000, Zagreb, Croatia
| | - Antonio Kokot
- Department of Anatomy and Neuroscience, Faculty of Medicine, J.J. Strossmayer University of Osijek, J.Huttlera 4, 31000, Osijek, Croatia
| | - Ranka Serventi Seiwerth
- Department of Pharmacology, School of Medicine, University of Zagreb, POB 916, Salata 11, 10000, Zagreb, Croatia
| | - Ivan Zoricic
- Department of Pharmacology, School of Medicine, University of Zagreb, POB 916, Salata 11, 10000, Zagreb, Croatia
| | - Alenka Boban Blagaic
- Department of Pharmacology, School of Medicine, University of Zagreb, POB 916, Salata 11, 10000, Zagreb, Croatia
| | - Sven Seiwerth
- Department of Pathology, School of Medicine, University of Zagreb, Salata 10, 10000, Zagreb, Croatia
| | - Predrag Sikiric
- Department of Pharmacology, School of Medicine, University of Zagreb, POB 916, Salata 11, 10000, Zagreb, Croatia.
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Perovic D, Kolenc D, Bilic V, Somun N, Drmic D, Elabjer E, Buljat G, Seiwerth S, Sikiric P. Stable gastric pentadecapeptide BPC 157 can improve the healing course of spinal cord injury and lead to functional recovery in rats. J Orthop Surg Res 2019; 14:199. [PMID: 31266512 PMCID: PMC6604284 DOI: 10.1186/s13018-019-1242-6] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/10/2019] [Accepted: 06/18/2019] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND We focused on the therapeutic effects of the stable gastric pentadecapeptide BPC 157 in spinal cord injury using a rat model. BPC 157, of which the LD1 has not been achieved, has been implemented as an anti-ulcer peptide in inflammatory bowel disease trials and recently in a multiple sclerosis trial. In animals, BPC 157 has an anti-inflammatory effect and therapeutic effects in functional recovery and the rescue of somatosensory neurons in the sciatic nerve after transection, upon brain injury after concussive trauma, and in severe encephalopathies. Additionally, BPC 157 affects various molecular pathways. METHODS Therefore, BPC 157 therapy was administered by a one-time intraperitoneal injection (BPC 157 (200 or 2 μg/kg) or 0.9% NaCl (5 ml/kg)) 10 min after injury. The injury procedure involved laminectomy (level L2-L3) and a 60-s compression (neurosurgical piston (60-66 g) of the exposed dural sac of the sacrocaudal spinal cord). Assessments were performed at 1, 4, 7, 15, 30, 90, 180, and 360 days after injury. RESULTS All of the injured rats that received BPC 157 exhibited consistent clinical improvement, increasingly better motor function of the tail, no autotomy, and resolved spasticity by day 15. BPC 157 application largely counteracted changes at the microscopic level, including the formation of vacuoles and the loss of axons in the white matter, the formation of edema and the loss of motoneurons in the gray matter, and a decreased number of large myelinated axons in the rat caudal nerve from day 7. EMG recordings showed a markedly lower motor unit potential in the tail muscle. CONCLUSION Axonal and neuronal necrosis, demyelination, and cyst formation were counteracted. The functional rescue provided by BPC 157 after spinal cord injury implies that BPC 157 therapy can impact all stages of the secondary injury phase.
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Affiliation(s)
- Darko Perovic
- Department of Pharmacology, School of Medicine, University of Zagreb, Salata 11, P.O. Box 916, 10000, Zagreb, Croatia
| | - Danijela Kolenc
- Department of Pathology, School of Medicine, University of Zagreb, Salata 9, 10000, Zagreb, Croatia
| | - Vide Bilic
- Department of Pharmacology, School of Medicine, University of Zagreb, Salata 11, P.O. Box 916, 10000, Zagreb, Croatia
| | - Nenad Somun
- Department of Pharmacology, School of Medicine, University of Zagreb, Salata 11, P.O. Box 916, 10000, Zagreb, Croatia
| | - Domagoj Drmic
- Department of Pharmacology, School of Medicine, University of Zagreb, Salata 11, P.O. Box 916, 10000, Zagreb, Croatia
| | - Esmat Elabjer
- Department of Pharmacology, School of Medicine, University of Zagreb, Salata 11, P.O. Box 916, 10000, Zagreb, Croatia
| | - Gojko Buljat
- Department of Pharmacology, School of Medicine, University of Zagreb, Salata 11, P.O. Box 916, 10000, Zagreb, Croatia
| | - Sven Seiwerth
- Department of Pathology, School of Medicine, University of Zagreb, Salata 9, 10000, Zagreb, Croatia
| | - Predrag Sikiric
- Department of Pharmacology, School of Medicine, University of Zagreb, Salata 11, P.O. Box 916, 10000, Zagreb, Croatia.
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Stable gastric pentadecapeptide BPC 157 in the therapy of the rats with bile duct ligation. Eur J Pharmacol 2019; 847:130-142. [PMID: 30690000 DOI: 10.1016/j.ejphar.2019.01.030] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2017] [Revised: 01/16/2019] [Accepted: 01/18/2019] [Indexed: 02/06/2023]
Abstract
Recently, stable gastric pentadecapeptide BPC 157 reversed the high MDA- and NO-tissue values to the healthy levels. Thereby, BPC 157 therapy cured rats with bile duct ligation (BDL) (sacrifice at 2, 4, 6, 8 week). BPC 157-medication (10 μg/kg, 10 ng/kg) was continuously in drinking water (0.16 μg/ml, 0.16 ng/ml, 12 ml/rat/day) since awakening from surgery, or since week 4. Intraperitoneal administration was first at 30 min post-ligation, last at 24 h before sacrifice. Local bath BPC 157 (10 µg/kg) with assessed immediate normalization of portal hypertension was given immediately after establishing portal hypertension values at 4, 6, 8 week. BPC 157 therapy markedly abated jaundice, snout, ears, paws, and yellow abdominal tegmentum in controls since 4th week, ascites, nodular, steatotic liver with large dilatation of main bile duct, increased liver and/or cyst weight, decreased body weight. BPC 157 counteracts the piecemeal necrosis, focal lytic necrosis, apoptosis and focal inflammation, disturbed cell proliferation (Ki-67-staining), cytoskeletal structure in the hepatic stellate cell (α-SMA staining), collagen presentation (Mallory staining). Likewise, counteraction includes increased AST, ALT, GGT, ALP, total bilirubin, direct and indirect and decreased albumin serum levels. As the end-result appear normalized MDA- and NO-tissue values, next to Western blot of NOS2 and NOS3 in the liver tissue, and decreased IL-6, TNF-α, IL-1β levels in liver tissue. Finally, although portal hypertension is sustained in BDL-rats, with BPC 157 therapy, portal hypertension in BDL-rats is either not even developed or rapidly abated, depending on the given BPC 157's regimen. Thus, BPC 157 may counteract liver fibrosis and portal hypertension.
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Drmic D, Samara M, Vidovic T, Malekinusic D, Antunovic M, Vrdoljak B, Ruzman J, Milkovic Perisa M, Horvat Pavlov K, Jeyakumar J, Seiwerth S, Sikiric P. Counteraction of perforated cecum lesions in rats: Effects of pentadecapeptide BPC 157, L-NAME and L-arginine. World J Gastroenterol 2018; 24:5462-5476. [PMID: 30622376 PMCID: PMC6319139 DOI: 10.3748/wjg.v24.i48.5462] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/19/2018] [Revised: 12/05/2018] [Accepted: 12/20/2018] [Indexed: 02/06/2023] Open
Abstract
AIM To study the counteraction of perforated cecum lesion using BPC 157 and nitric oxide (NO) system agents.
METHODS Alongside with the agents’ application (after 1 min, medication (/kg, 10 mL/2 min bath/rat) includes: BPC 157 (10 μg), L-NAME (5 mg), L-arginine (100mg) alone or combined, and saline baths (controls)) on the rat perforate cecum injury, we continuously assessed the gross reappearance of the vessels (USB microcamera) quickly propagating toward the defect at the cecum surface, defect contraction, bleeding attenuation, MDA- and NO-levels in cecum tissue at 15 min, and severity of cecum lesions and adhesions at 1 and 7 d.
RESULTS Post-injury, during/after a saline bath, the number of vessels was significantly reduced, the defect was slightly narrowed, bleeding was significant and MDA-levels increased and NO-levels decreased. BPC 157 bath: the vessel presentation was markedly increased, the defect was noticeably narrowed, the bleeding time was shortened and MDA- and NO-levels remained normal. L-NAME: reduced vessel presentation but not more than the control, did not change defect and shortened bleeding. L-arginine: exhibited less vessel reduction, did not change the defect and prolonged bleeding. In combination, mutual counteraction occurred (L-NAME + L-arginine) or the presentation was similar to that of BPC 157 rats (BPC 157 + L-NAME; BPC 157 + L-arginine; BPC 157 + L-NAME + L-arginine), except the defect did not change. Thereby at day 1 and 7, saline, L-NAME, L-arginine and L-NAME + L-arginine failed (defect was still open and large adhesions present).
CONCLUSION The therapeutic effect was achieved with BPC 157 alone or in combination with L-NAME and L-arginine as it was able to consolidate the stimulating and inhibiting effects of the NO-system towards more effective healing recruiting vessels.
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Affiliation(s)
- Domagoj Drmic
- Departments of Pharmacology and Pathology, Medical Faculty University of Zagreb, Zagreb 10000, Croatia
| | - Mariam Samara
- Departments of Pharmacology and Pathology, Medical Faculty University of Zagreb, Zagreb 10000, Croatia
| | - Tinka Vidovic
- Departments of Pharmacology and Pathology, Medical Faculty University of Zagreb, Zagreb 10000, Croatia
| | - Dominik Malekinusic
- Departments of Pharmacology and Pathology, Medical Faculty University of Zagreb, Zagreb 10000, Croatia
| | - Marko Antunovic
- Departments of Pharmacology and Pathology, Medical Faculty University of Zagreb, Zagreb 10000, Croatia
| | - Borna Vrdoljak
- Departments of Pharmacology and Pathology, Medical Faculty University of Zagreb, Zagreb 10000, Croatia
| | - Jelena Ruzman
- Departments of Pharmacology and Pathology, Medical Faculty University of Zagreb, Zagreb 10000, Croatia
| | - Marija Milkovic Perisa
- Departments of Pharmacology and Pathology, Medical Faculty University of Zagreb, Zagreb 10000, Croatia
| | - Katarina Horvat Pavlov
- Departments of Pharmacology and Pathology, Medical Faculty University of Zagreb, Zagreb 10000, Croatia
| | - Jerusha Jeyakumar
- Departments of Pharmacology and Pathology, Medical Faculty University of Zagreb, Zagreb 10000, Croatia
| | - Sven Seiwerth
- Departments of Pharmacology and Pathology, Medical Faculty University of Zagreb, Zagreb 10000, Croatia
| | - Predrag Sikiric
- Departments of Pharmacology and Pathology, Medical Faculty University of Zagreb, Zagreb 10000, Croatia
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Amic F, Drmic D, Bilic Z, Krezic I, Zizek H, Peklic M, Klicek R, Pajtak A, Amic E, Vidovic T, Rakic M, Milkovic Perisa M, Horvat Pavlov K, Kokot A, Tvrdeic A, Boban Blagaic A, Zovak M, Seiwerth S, Sikiric P. Bypassing major venous occlusion and duodenal lesions in rats, and therapy with the stable gastric pentadecapeptide BPC 157, L-NAME and L-arginine. World J Gastroenterol 2018; 24:5366-5378. [PMID: 30598581 PMCID: PMC6305534 DOI: 10.3748/wjg.v24.i47.5366] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/06/2018] [Revised: 11/26/2018] [Accepted: 12/01/2018] [Indexed: 02/06/2023] Open
Abstract
AIM To investigate whether duodenal lesions induced by major venous occlusions can be attenuated by BPC 157 regardless nitric oxide (NO) system involvement.
METHODS Male Wistar rats underwent superior anterior pancreaticoduodenal vein (SAPDV)-ligation and were treated with a bath at the ligated SAPDV site (BPC 157 10 μg, 10 ng/kg per 1 mL bath/rat; L-NAME 5 mg/kg per 1 mL bath/rat; L-arginine 100 mg/kg per 1 mL bath/rat, alone and/or together; or BPC 157 10 μg/kg instilled into the rat stomach, at 1 min ligation-time). We recorded the vessel presentation (filled/appearance or emptied/disappearance) between the 5 arcade vessels arising from the SAPDV on the ventral duodenum side, the inferior anterior pancreaticoduodenal vein (IAPDV) and superior mesenteric vein (SMV) as bypassing vascular pathway to document the duodenal lesions presentation; increased NO- and oxidative stress [malondialdehyde (MDA)]-levels in duodenum.
RESULTS Unlike the severe course in the SAPDV-ligated controls, after BPC 157 application, the rats exhibited strong attenuation of the mucosal lesions and serosal congestion, improved vessel presentation, increased interconnections, increased branching by more than 60% from the initial value, the IAPDV and SMV were not congested. Interestingly, after 5 min and 30 min of L-NAME and L-arginine treatment alone, decreased mucosal and serosal duodenal lesions were observed; their effect was worsened at 24 h, and no effect on the collateral vessels and branching was seen. Together, L-NAME+L-arginine antagonized each other’s response, and thus, there was an NO-related effect. With BPC 157, all SAPDV-ligated rats receiving L-NAME and/or L-arginine appeared similar to the rats treated with BPC 157 alone. Also, BPC 157 in SAPDV-ligated rats normalized levels of NO and MDA, two oxidative stress markers, in duodenal tissues.
CONCLUSION BPC 157, rapidly bypassing occlusion, rescued the original duodenal flow through IAPDV to SMV flow, an effect related to the NO system and reduction of free radical formation.
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Affiliation(s)
- Fedor Amic
- Department of Pharmacology, Medical Faculty, University of Zagreb, Zagreb 10000, Croatia
- Department of Pathology, Medical Faculty, University of Zagreb, Zagreb 10000, Croatia
| | - Domagoj Drmic
- Department of Pharmacology, Medical Faculty, University of Zagreb, Zagreb 10000, Croatia
- Department of Pathology, Medical Faculty, University of Zagreb, Zagreb 10000, Croatia
| | - Zdenko Bilic
- Department of Pharmacology, Medical Faculty, University of Zagreb, Zagreb 10000, Croatia
- Department of Pathology, Medical Faculty, University of Zagreb, Zagreb 10000, Croatia
| | - Ivan Krezic
- Department of Pharmacology, Medical Faculty, University of Zagreb, Zagreb 10000, Croatia
- Department of Pathology, Medical Faculty, University of Zagreb, Zagreb 10000, Croatia
| | - Helena Zizek
- Department of Pharmacology, Medical Faculty, University of Zagreb, Zagreb 10000, Croatia
- Department of Pathology, Medical Faculty, University of Zagreb, Zagreb 10000, Croatia
| | - Marina Peklic
- Department of Pharmacology, Medical Faculty, University of Zagreb, Zagreb 10000, Croatia
- Department of Pathology, Medical Faculty, University of Zagreb, Zagreb 10000, Croatia
| | - Robert Klicek
- Department of Pharmacology, Medical Faculty, University of Zagreb, Zagreb 10000, Croatia
- Department of Pathology, Medical Faculty, University of Zagreb, Zagreb 10000, Croatia
| | - Alen Pajtak
- Department of Pharmacology, Medical Faculty, University of Zagreb, Zagreb 10000, Croatia
- Department of Pathology, Medical Faculty, University of Zagreb, Zagreb 10000, Croatia
| | - Enio Amic
- Department of Pharmacology, Medical Faculty, University of Zagreb, Zagreb 10000, Croatia
- Department of Pathology, Medical Faculty, University of Zagreb, Zagreb 10000, Croatia
| | - Tinka Vidovic
- Department of Pharmacology, Medical Faculty, University of Zagreb, Zagreb 10000, Croatia
- Department of Pathology, Medical Faculty, University of Zagreb, Zagreb 10000, Croatia
| | - Mislav Rakic
- Department of Pharmacology, Medical Faculty, University of Zagreb, Zagreb 10000, Croatia
- Department of Pathology, Medical Faculty, University of Zagreb, Zagreb 10000, Croatia
| | - Marija Milkovic Perisa
- Department of Pharmacology, Medical Faculty, University of Zagreb, Zagreb 10000, Croatia
- Department of Pathology, Medical Faculty, University of Zagreb, Zagreb 10000, Croatia
| | - Katarina Horvat Pavlov
- Department of Pharmacology, Medical Faculty, University of Zagreb, Zagreb 10000, Croatia
- Department of Pathology, Medical Faculty, University of Zagreb, Zagreb 10000, Croatia
| | - Antonio Kokot
- Department of Pharmacology, Medical Faculty, University of Zagreb, Zagreb 10000, Croatia
- Department of Pathology, Medical Faculty, University of Zagreb, Zagreb 10000, Croatia
| | - Ante Tvrdeic
- Department of Pharmacology, Medical Faculty, University of Zagreb, Zagreb 10000, Croatia
- Department of Pathology, Medical Faculty, University of Zagreb, Zagreb 10000, Croatia
| | - Alenka Boban Blagaic
- Department of Pharmacology, Medical Faculty, University of Zagreb, Zagreb 10000, Croatia
- Department of Pathology, Medical Faculty, University of Zagreb, Zagreb 10000, Croatia
| | - Mario Zovak
- Department of Pharmacology, Medical Faculty, University of Zagreb, Zagreb 10000, Croatia
- Department of Pathology, Medical Faculty, University of Zagreb, Zagreb 10000, Croatia
| | - Sven Seiwerth
- Department of Pharmacology, Medical Faculty, University of Zagreb, Zagreb 10000, Croatia
- Department of Pathology, Medical Faculty, University of Zagreb, Zagreb 10000, Croatia
| | - Predrag Sikiric
- Department of Pharmacology, Medical Faculty, University of Zagreb, Zagreb 10000, Croatia
- Department of Pathology, Medical Faculty, University of Zagreb, Zagreb 10000, Croatia
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Cytoprotective Mechanism of the Novel Gastric Peptide BPC157 in Gastrointestinal Tract and Cultured Enteric Neurons and Glial Cells. Neurosci Bull 2018; 35:167-170. [PMID: 30116973 DOI: 10.1007/s12264-018-0269-8] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2018] [Accepted: 04/25/2018] [Indexed: 12/11/2022] Open
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Vukojević J, Siroglavić M, Kašnik K, Kralj T, Stanćić D, Kokot A, Kolarić D, Drmić D, Sever AZ, Barišić I, Šuran J, Bojić D, Patrlj MH, Sjekavica I, Pavlov KH, Vidović T, Vlainić J, Stupnišek M, Seiwerth S, Sikirić P. Rat inferior caval vein (ICV) ligature and particular new insights with the stable gastric pentadecapeptide BPC 157. Vascul Pharmacol 2018; 106:54-66. [PMID: 29510201 DOI: 10.1016/j.vph.2018.02.010] [Citation(s) in RCA: 37] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2017] [Revised: 11/10/2017] [Accepted: 02/25/2018] [Indexed: 02/07/2023]
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Tlak Gajger I, Ribarić J, Smodiš Škerl M, Vlainić J, Sikirić P. Stable gastric pentadecapeptide BPC 157 in honeybee (Apis mellifera) therapy, to control Nosema ceranae invasions in apiary conditions. J Vet Pharmacol Ther 2018; 41:614-621. [PMID: 29682749 DOI: 10.1111/jvp.12509] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2017] [Accepted: 03/23/2018] [Indexed: 02/07/2023]
Abstract
Nosema ceranae can cause major problems, such as immune suppression, gut epithelial cell degeneration, reduced honeybee lifespan, or suddenly colony collapse. As a novel approach in therapy, we hypothesize the stable gastric pentadecapeptide BPC 157 in honeybee therapy, to control N. ceranae invasions in apiary conditions: BPC 157 treated sugar syrup (0.25 L sugar syrup supplemented with 0.1 μg/ml BPC 157), as well as the pure sugar syrup (0.25 L sugar syrup; control), was administered to honeybee colonies in feeders situated under the roof of the hives, during 21 consecutive days, at the end of beekeeping season. The strength of honeybee colonies was increased 20 and 30 days after initial feeding with BPC 157 supplement (Day 1, 36.100 ± 698; Day 20, 64.860 ± 468; Day 30, 53.214 ± 312 estimated number of honeybees), in field conditions. The similar successful outcome occurs with the N. ceranae spore loads counted in the homogenates of sampled adult honeybees (Day 1, 6.286 ± 2.336; Day 20, 3.753 ± 1.835; Day 30, 2.005 ± 1.534 million spores/bee). Accordingly, with the noted increased strength of the colonies fed with sugar syrup supplemented with BPC 157, the number of N. ceranae spores per honeybee gradually decreased as well. Besides, honeybees infected with N. ceranae fed with sugar syrup exhibited severe damage of midgut wall layers and epithelial cells. By contrast, in honeybees infected with N. ceranae fed with sugar syrup supplemented with BPC 157, all damages were markedly attenuated, damages of the outer muscular coat, in particular. In conclusion, the results of the first field trial on diseased honeybee colonies with BPC 157 indicate significant therapeutic effects with the used oral therapy with BPC 157 supplementation.
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Affiliation(s)
- I Tlak Gajger
- Department for Biology and Pathology of Fish and Bees, Laboratory for Honeybee Diseases - NRL, University of Zagreb Faculty of Veterinary Medicine, Zagreb, Croatia
| | - J Ribarić
- Ministry of Agriculture Veterinary and Food Safety Directorate, Zagreb, Croatia
| | | | - J Vlainić
- Institute Ruđer Bošković, Zagreb, Croatia
| | - P Sikirić
- University of Zagreb Medical Faculty, Zagreb, Croatia
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Duzel A, Vlainic J, Antunovic M, Malekinusic D, Vrdoljak B, Samara M, Gojkovic S, Krezic I, Vidovic T, Bilic Z, Knezevic M, Sever M, Lojo N, Kokot A, Kolovrat M, Drmic D, Vukojevic J, Kralj T, Kasnik K, Siroglavic M, Seiwerth S, Sikiric P. Stable gastric pentadecapeptide BPC 157 in the treatment of colitis and ischemia and reperfusion in rats: New insights. World J Gastroenterol 2017; 23:8465-8488. [PMID: 29358856 PMCID: PMC5752708 DOI: 10.3748/wjg.v23.i48.8465] [Citation(s) in RCA: 51] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/02/2017] [Revised: 10/31/2017] [Accepted: 11/27/2017] [Indexed: 02/06/2023] Open
Abstract
AIM To provide new insights in treatment of colitis and ischemia and reperfusion in rats using stable gastric pentadecapeptide BPC 157.
METHODS Medication [BPC 157, L-NAME, L-arginine (alone/combined), saline] was bath at the blood deprived colon segment. During reperfusion, medication was BPC 157 or saline. We recorded (USB microscope camera) vessel presentation through next 15 min of ischemic colitis (IC-rats) or reperfusion (removed ligations) (IC + RL-rats); oxidative stress as MDA (increased (IC- and IC + RL-rats)) and NO levels (decreased (IC-rats); increased (IC + RL-rats)) in colon tissue. IC + OB-rats [IC-rats had additional colon obstruction (OB)] for 3 d (IC + OB-rats), then received BPC 157 bath.
RESULTS Commonly, in colon segment (25 mm, 2 ligations on left colic artery and vein, 3 arcade vessels within ligated segment), in IC-, IC + RL-, IC + OB-rats, BPC 157 (10 μg/kg) bath (1 mL/rat) increased vessel presentation, inside/outside arcade interconnections quickly reappeared, mucosal folds were preserved and the pale areas were small and markedly reduced. BPC 157 counteracted worsening effects induced by L-NAME (5 mg) and L-arginine (100 mg). MDA- and NO-levels were normal in BPC 157 treated IC-rats and IC + RL-rats. In addition, on day 10, BPC 157-treated IC + OB-rats presented almost completely spared mucosa with very small pale areas and no gross mucosal defects; the treated colon segment was of normal diameter, and only small adhesions were present.
CONCLUSION BPC 157 is a fundamental treatment that quickly restores blood supply to the ischemically injured area and rapidly activates collaterals. This effect involves the NO system.
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Affiliation(s)
- Antonija Duzel
- Departments of Pharmacology and Pathology, Medical Faculty University of Zagreb, Zagreb 10000, Croatia
- Medical Faculty J.J. Strossmayer University of Osijek, Osijek, Croatia; Rudjer Boskovic Institute, Department of Molecular Medicine, Zagreb 10000, Croatia
| | - Josipa Vlainic
- Departments of Pharmacology and Pathology, Medical Faculty University of Zagreb, Zagreb 10000, Croatia
- Medical Faculty J.J. Strossmayer University of Osijek, Osijek, Croatia; Rudjer Boskovic Institute, Department of Molecular Medicine, Zagreb 10000, Croatia
| | - Marko Antunovic
- Departments of Pharmacology and Pathology, Medical Faculty University of Zagreb, Zagreb 10000, Croatia
- Medical Faculty J.J. Strossmayer University of Osijek, Osijek, Croatia; Rudjer Boskovic Institute, Department of Molecular Medicine, Zagreb 10000, Croatia
| | - Dominik Malekinusic
- Departments of Pharmacology and Pathology, Medical Faculty University of Zagreb, Zagreb 10000, Croatia
- Medical Faculty J.J. Strossmayer University of Osijek, Osijek, Croatia; Rudjer Boskovic Institute, Department of Molecular Medicine, Zagreb 10000, Croatia
| | - Borna Vrdoljak
- Departments of Pharmacology and Pathology, Medical Faculty University of Zagreb, Zagreb 10000, Croatia
- Medical Faculty J.J. Strossmayer University of Osijek, Osijek, Croatia; Rudjer Boskovic Institute, Department of Molecular Medicine, Zagreb 10000, Croatia
| | - Mariam Samara
- Departments of Pharmacology and Pathology, Medical Faculty University of Zagreb, Zagreb 10000, Croatia
- Medical Faculty J.J. Strossmayer University of Osijek, Osijek, Croatia; Rudjer Boskovic Institute, Department of Molecular Medicine, Zagreb 10000, Croatia
| | - Slaven Gojkovic
- Departments of Pharmacology and Pathology, Medical Faculty University of Zagreb, Zagreb 10000, Croatia
- Medical Faculty J.J. Strossmayer University of Osijek, Osijek, Croatia; Rudjer Boskovic Institute, Department of Molecular Medicine, Zagreb 10000, Croatia
| | - Ivan Krezic
- Departments of Pharmacology and Pathology, Medical Faculty University of Zagreb, Zagreb 10000, Croatia
- Medical Faculty J.J. Strossmayer University of Osijek, Osijek, Croatia; Rudjer Boskovic Institute, Department of Molecular Medicine, Zagreb 10000, Croatia
| | - Tinka Vidovic
- Departments of Pharmacology and Pathology, Medical Faculty University of Zagreb, Zagreb 10000, Croatia
- Medical Faculty J.J. Strossmayer University of Osijek, Osijek, Croatia; Rudjer Boskovic Institute, Department of Molecular Medicine, Zagreb 10000, Croatia
| | - Zdenko Bilic
- Departments of Pharmacology and Pathology, Medical Faculty University of Zagreb, Zagreb 10000, Croatia
- Medical Faculty J.J. Strossmayer University of Osijek, Osijek, Croatia; Rudjer Boskovic Institute, Department of Molecular Medicine, Zagreb 10000, Croatia
| | - Mario Knezevic
- Departments of Pharmacology and Pathology, Medical Faculty University of Zagreb, Zagreb 10000, Croatia
- Medical Faculty J.J. Strossmayer University of Osijek, Osijek, Croatia; Rudjer Boskovic Institute, Department of Molecular Medicine, Zagreb 10000, Croatia
| | - Marko Sever
- Departments of Pharmacology and Pathology, Medical Faculty University of Zagreb, Zagreb 10000, Croatia
- Medical Faculty J.J. Strossmayer University of Osijek, Osijek, Croatia; Rudjer Boskovic Institute, Department of Molecular Medicine, Zagreb 10000, Croatia
| | - Nermin Lojo
- Departments of Pharmacology and Pathology, Medical Faculty University of Zagreb, Zagreb 10000, Croatia
- Medical Faculty J.J. Strossmayer University of Osijek, Osijek, Croatia; Rudjer Boskovic Institute, Department of Molecular Medicine, Zagreb 10000, Croatia
| | - Antonio Kokot
- Departments of Pharmacology and Pathology, Medical Faculty University of Zagreb, Zagreb 10000, Croatia
- Medical Faculty J.J. Strossmayer University of Osijek, Osijek, Croatia; Rudjer Boskovic Institute, Department of Molecular Medicine, Zagreb 10000, Croatia
| | - Marijan Kolovrat
- Departments of Pharmacology and Pathology, Medical Faculty University of Zagreb, Zagreb 10000, Croatia
- Medical Faculty J.J. Strossmayer University of Osijek, Osijek, Croatia; Rudjer Boskovic Institute, Department of Molecular Medicine, Zagreb 10000, Croatia
| | - Domagoj Drmic
- Departments of Pharmacology and Pathology, Medical Faculty University of Zagreb, Zagreb 10000, Croatia
- Medical Faculty J.J. Strossmayer University of Osijek, Osijek, Croatia; Rudjer Boskovic Institute, Department of Molecular Medicine, Zagreb 10000, Croatia
| | - Jaksa Vukojevic
- Departments of Pharmacology and Pathology, Medical Faculty University of Zagreb, Zagreb 10000, Croatia
- Medical Faculty J.J. Strossmayer University of Osijek, Osijek, Croatia; Rudjer Boskovic Institute, Department of Molecular Medicine, Zagreb 10000, Croatia
| | - Tamara Kralj
- Departments of Pharmacology and Pathology, Medical Faculty University of Zagreb, Zagreb 10000, Croatia
- Medical Faculty J.J. Strossmayer University of Osijek, Osijek, Croatia; Rudjer Boskovic Institute, Department of Molecular Medicine, Zagreb 10000, Croatia
| | - Katarina Kasnik
- Departments of Pharmacology and Pathology, Medical Faculty University of Zagreb, Zagreb 10000, Croatia
- Medical Faculty J.J. Strossmayer University of Osijek, Osijek, Croatia; Rudjer Boskovic Institute, Department of Molecular Medicine, Zagreb 10000, Croatia
| | - Marko Siroglavic
- Departments of Pharmacology and Pathology, Medical Faculty University of Zagreb, Zagreb 10000, Croatia
- Medical Faculty J.J. Strossmayer University of Osijek, Osijek, Croatia; Rudjer Boskovic Institute, Department of Molecular Medicine, Zagreb 10000, Croatia
| | - Sven Seiwerth
- Departments of Pharmacology and Pathology, Medical Faculty University of Zagreb, Zagreb 10000, Croatia
- Medical Faculty J.J. Strossmayer University of Osijek, Osijek, Croatia; Rudjer Boskovic Institute, Department of Molecular Medicine, Zagreb 10000, Croatia
| | - Predrag Sikiric
- Departments of Pharmacology and Pathology, Medical Faculty University of Zagreb, Zagreb 10000, Croatia
- Medical Faculty J.J. Strossmayer University of Osijek, Osijek, Croatia; Rudjer Boskovic Institute, Department of Molecular Medicine, Zagreb 10000, Croatia
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Belosic Halle Z, Vlainic J, Drmic D, Strinic D, Luetic K, Sucic M, Medvidovic-Grubisic M, Pavelic Turudic T, Petrovic I, Seiwerth S, Sikiric P. Class side effects: decreased pressure in the lower oesophageal and the pyloric sphincters after the administration of dopamine antagonists, neuroleptics, anti-emetics, L-NAME, pentadecapeptide BPC 157 and L-arginine. Inflammopharmacology 2017; 25:10.1007/s10787-017-0358-8. [PMID: 28516373 DOI: 10.1007/s10787-017-0358-8] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2016] [Accepted: 05/05/2017] [Indexed: 12/13/2022]
Abstract
The ulcerogenic potential of dopamine antagonists and L-NAME in rats provides unresolved issues of anti-emetic neuroleptic application in both patients and experimental studies. Therefore, in a 1-week study, we examined the pressures within the lower oesophageal and the pyloric sphincters in rats [assessed manometrically (cm H2O)] after dopamine neuroleptics/prokinetics, L-NAME, L-arginine and stable gastric pentadecapeptide BPC 157 were administered alone and/or in combination. Medication (/kg) was given once daily intraperitoneally throughout the 7 days, with the last dose at 24 h before pressure assessment. Given as individual agents to healthy rats, all dopamine antagonists (central [haloperidol (6.25 mg, 16 mg, 25 mg), fluphenazine (5 mg), levomepromazine (50 mg), chlorpromazine (10 mg), quetiapine (10 mg), olanzapine (5 mg), clozapine (100 mg), sulpiride (160 mg), metoclopramide (25 mg)) and peripheral(domperidone (10 mg)], L-NAME (5 mg) and L-arginine (100 mg) decreased the pressure within both sphincters. As a common effect, this decreased pressure was rescued, dose-dependently, by BPC 157 (10 µg, 10 ng) (also note that L-arginine and L-NAME given together antagonized each other's responses). With haloperidol, L-NAME worsened both the lower oesophageal and the pyloric sphincter pressure, while L-arginine ameliorated lower oesophageal sphincter but not pyloric sphincter pressure, and antagonized L-NAME effect. With domperidone, L-arginine originally had no effect, while L-NAME worsened pyloric sphincter pressure. This effect was opposed by L-arginine. All these effects were further reversed towards a stronger beneficial effect, close to normal pressure values, by the addition of BPC 157. In addition, NO level was determined in plasma, sphincters and brain tissue. Thiobarbituric acid reactive substances (TBARS) were also assessed. Haloperidol increased NO levels (in both sphincters, the plasma and brain), consistently producing increased TBARS levels in the plasma, sphincters and brain tissues. These effects were all counteracted by BPC 157 administration. In conclusion, we revealed that BPC 157 counteracts the anti-emetic neuroleptic class side effect of decreased pressure in sphincters and the dopamine/NO-system/BPC 157 relationship.
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Affiliation(s)
- Zeljka Belosic Halle
- Department of Pharmacology, School of Medicine, University of Zagreb, Salata 11, P.O. Box 916, 10000, Zagreb, Croatia
- Faculty of Medicine, J.J. Strossmayer University of Osijek, J. Huttlera 4, 31000, Osijek, Croatia
| | - Josipa Vlainic
- Laboratory of Molecular Neuropharmacology, Division of Molecular Medicine, Rudjer Boskovic Institute, 10000, Zagreb, Croatia
| | - Domagoj Drmic
- Department of Pharmacology, School of Medicine, University of Zagreb, Salata 11, P.O. Box 916, 10000, Zagreb, Croatia
| | - Dean Strinic
- Department of Pharmacology, School of Medicine, University of Zagreb, Salata 11, P.O. Box 916, 10000, Zagreb, Croatia
- Faculty of Medicine, J.J. Strossmayer University of Osijek, J. Huttlera 4, 31000, Osijek, Croatia
| | - Kresimir Luetic
- Department of Pharmacology, School of Medicine, University of Zagreb, Salata 11, P.O. Box 916, 10000, Zagreb, Croatia
- Faculty of Medicine, J.J. Strossmayer University of Osijek, J. Huttlera 4, 31000, Osijek, Croatia
| | - Mario Sucic
- Department of Pharmacology, School of Medicine, University of Zagreb, Salata 11, P.O. Box 916, 10000, Zagreb, Croatia
- Faculty of Medicine, J.J. Strossmayer University of Osijek, J. Huttlera 4, 31000, Osijek, Croatia
| | - Maria Medvidovic-Grubisic
- Department of Pharmacology, School of Medicine, University of Zagreb, Salata 11, P.O. Box 916, 10000, Zagreb, Croatia
| | - Tatjana Pavelic Turudic
- Department of Pharmacology, School of Medicine, University of Zagreb, Salata 11, P.O. Box 916, 10000, Zagreb, Croatia
- Faculty of Medicine, J.J. Strossmayer University of Osijek, J. Huttlera 4, 31000, Osijek, Croatia
| | - Igor Petrovic
- Department of Pharmacology, School of Medicine, University of Zagreb, Salata 11, P.O. Box 916, 10000, Zagreb, Croatia
| | - Sven Seiwerth
- Department of Pathology, School of Medicine, University of Zagreb, Salata 10, 10000, Zagreb, Croatia
| | - Predrag Sikiric
- Department of Pharmacology, School of Medicine, University of Zagreb, Salata 11, P.O. Box 916, 10000, Zagreb, Croatia.
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Cyclophosphamide induced stomach and duodenal lesions as a NO-system disturbance in rats: L-NAME, L-arginine, stable gastric pentadecapeptide BPC 157. Inflammopharmacology 2017; 25:255-264. [PMID: 28255738 DOI: 10.1007/s10787-017-0330-7] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2016] [Accepted: 02/15/2017] [Indexed: 12/13/2022]
Abstract
We revealed a new point with cyclophosphamide (150 mg/kg/day intraperitoneally for 7 days): we counteracted both rat stomach and duodenal ulcers and increased NO- and MDA-levels in these tissues. As a NO-system effect, BPC 157 therapy (10 µg/kg, 10 ng/kg, intraperitoneally once a day or in drinking water, till the sacrifice) attenuated the increased NO- and MDA-levels and nullified, in rats, severe cyclophosphamide-ulcers and even stronger stomach and duodenal lesions after cyclophosphamide + L-NAME (5 mg/kg intraperitoneally once a day). L-arginine (100 mg/kg intraperitoneally once a day not effective alone) led L-NAME-values only to the control values (cyclophosphamide + L-NAME + L-arginine-rats). Briefly, rats were sacrificed at 24 h after last administration on days 1, 2, 3, or 7, and assessment included sum of longest lesions diameters (mm) in the stomach and duodenum, oxidative stress by quantifying thiobarbituric acid reactivity as malondialdehyde equivalents (MDA), NO in stomach and duodenal tissue samples using the Griess reaction. All these parameters were highly exaggerated in rats who underwent cyclophosphamide treatment. We identified high MDA-tissue values, high NO-tissue values, ulcerogenic and beneficial potential in cyclophosphamide-L-NAME-L-arginine-BPC 157 relationships. This suggests that in cyclophosphamide damaged rats, NO excessive release generated by the inducible isozyme, damages the vascular wall and other tissue cells, especially in combination with reactive oxygen intermediates, while failing endothelial production and resulting in further aggravation by L-NAME which was inhibited by L-arginine. Finally, BPC 157, due to its special relations with NO-system, may both lessen increased MDA- and NO-tissues values and counteract effects of both cyclophosphamide and L-NAME on stomach and duodenal lesions.
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Sikiric P, Seiwerth S, Rucman R, Kolenc D, Vuletic LB, Drmic D, Grgic T, Strbe S, Zukanovic G, Crvenkovic D, Madzarac G, Rukavina I, Sucic M, Baric M, Starcevic N, Krstonijevic Z, Bencic ML, Filipcic I, Rokotov DS, Vlainic J. Brain-gut Axis and Pentadecapeptide BPC 157: Theoretical and Practical Implications. Curr Neuropharmacol 2017; 14:857-865. [PMID: 27138887 PMCID: PMC5333585 DOI: 10.2174/1570159x13666160502153022] [Citation(s) in RCA: 42] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2016] [Revised: 03/17/2016] [Accepted: 04/21/2016] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND Brain-gut interaction involves, among others, peptidergic growth factors which are native in GI tract and have strong antiulcer potency and thus could from periphery beneficially affect CNS-disorders. We focused on the stable gastric pentadecapeptide BPC 157, an antiulcer peptidergic agent, safe in inflammatory bowel disease trials and now in multiple sclerosis trial, native and stable in human gastric juice. METHODS Review of our research on BPC 157 in terms of brain-gut axis. RESULTS BPC 157 may serve as a novel mediator of Robert's cytoprotection, involved in maintaining of GI mucosa integrity, with no toxic effect. BPC 157 was successful in the therapy of GI tract, periodontitis, liver and pancreas lesions, and in the healing of various tissues and wounds. Stimulated Egr-1 gene, NAB2, FAK-paxillin and JAK-2 pathways are hitherto implicated. Initially corresponding beneficial central influence was seen when BPC 157 was given peripherally and a serotonin release in particular brain areas, mostly nigrostriatal, was changed. BPC 157 modulates serotonergic and dopaminergic systems, beneficially affects various behavioral disturbances that otherwise appeared due to specifically (over)stimulated/damaged neurotransmitters systems. Besides, BPC 157 has neuroprotective effects: protects somatosensory neurons; peripheral nerve regeneration appearent after transection; after traumatic brain injury counteracts the otherwise progressing course, in rat spinal cord compression with tail paralysis, axonal and neuronal necrosis, demyelination, cyst formation and rescues tail function in both short-terms and long-terms; after NSAIDs or insulin overdose or cuprizone encephalopathies were attenuated along with GI, liver and vascular injuries. CONCLUSION BPC 157, a gastric peptide, may serve as remedy in various CNS-disorders.
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Affiliation(s)
- Predrag Sikiric
- Medical Faculty, University of Zagreb, Šalata 3, 10000 Zagreb, Croatia
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Tsang SW, Auyeung KKW, Bian ZX, Ko JKS. Pathogenesis, Experimental Models and Contemporary Pharmacotherapy of Irritable Bowel Syndrome: Story About the Brain-Gut Axis. Curr Neuropharmacol 2017; 14:842-856. [PMID: 27009115 PMCID: PMC5333584 DOI: 10.2174/1570159x14666160324144154] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2015] [Revised: 02/07/2016] [Accepted: 03/22/2016] [Indexed: 11/22/2022] Open
Abstract
Background Although the precise pathophysiology of irritable bowel syndrome (IBS) remains unknown, it is generally considered to be a disorder of the brain-gut axis, representing the disruption of communication between the brain and the digestive system. The present review describes advances in understanding the pathophysiology and experimental approaches in studying IBS, as well as providing an update of the therapies targeting brain-gut axis in the treatment of the disease. Methods Causal factors of IBS are reviewed. Following this, the preclinical experimental models of IBS will be introduced. Besides, both current and future therapeutic approaches of IBS will be discussed. Results When signal of the brain-gut axis becomes misinterpreted, it may lead to dysregulation of both central and enteric nervous systems, altered intestinal motility, increased visceral sensitivity and consequently contributing to the development of IBS. Interference of the brain-gut axis can be modulated by various psychological and environmental factors. Although there is no existing animal experiment that can represent this complex multifactorial disease, these in vivo models are clinically relevant readouts of gastrointestinal functions being essential to the identification of effective treatments of IBS symptoms as well as their molecular targets. Understanding the brain-gut axis is essential in developing the effective therapy for IBS. Therapies include improvement of GI motor functions, relief of visceral hypersensitivity and pain, attenuation of autonomic dysfunctions and suppression of mucosal immune activation. Conclusion Target-oriented therapies that provide symptomatic, psychological and physiological benefits could surely help to improve the quality of life of IBS patients.
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Affiliation(s)
| | | | | | - J K S Ko
- Center for Cancer and Inflammation Research, School of Chinese Medicine, Hong Kong Baptist University, 7 Baptist University Road, Kowloon Tong, Hong Kong SAR, China
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Djakovic Z, Djakovic I, Cesarec V, Madzarac G, Becejac T, Zukanovic G, Drmic D, Batelja L, Zenko Sever A, Kolenc D, Pajtak A, Knez N, Japjec M, Luetic K, Stancic-Rokotov D, Seiwerth S, Sikiric P. Esophagogastric anastomosis in rats: Improved healing by BPC 157 and L-arginine, aggravated by L-NAME. World J Gastroenterol 2016; 22:9127-9140. [PMID: 27895400 PMCID: PMC5107594 DOI: 10.3748/wjg.v22.i41.9127] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/01/2016] [Revised: 08/28/2016] [Accepted: 09/28/2016] [Indexed: 02/06/2023] Open
Abstract
AIM To cure typically life-threatening esophagogastric anastomosis in rats, lacking anastomosis healing and sphincter function rescue, in particular.
METHODS Because we assume esophagogastric fistulas represent a particular NO-system disability, we attempt to identify the benefits of anti-ulcer stable gastric pentadecapeptide BPC 157, which was in trials for ulcerative colitis and currently for multiple sclerosis, in rats with esophagocutaneous fistulas. Previously, BPC 157 therapies have promoted the healing of intestinal anastomosis and fistulas, and esophagitis and gastric lesions, along with rescued sphincter function. Additionally, BPC 157 particularly interacts with the NO-system. In the 4 d after esophagogastric anastomosis creation, rats received medication (/kg intraperitoneally once daily: BPC 157 (10 μg, 10 ng), L-NAME (5 mg), or L-arginine (100 mg) alone and/or combined or BPC 157 (10 μg, 10 ng) in drinking water). For rats underwent esophagogastric anastomosis, daily assessment included progressive stomach damage (sum of the longest diameters, mm), esophagitis (scored 0-5), weak anastomosis (mL H2O before leak), low pressure in esophagus at anastomosis and in the pyloric sphincter (cm H2O), progressive weight loss (g) and mortality. Immediate effect assessed blood vessels disappearance (scored 0-5) at the stomach surface immediately after anastomosis creation.
RESULTS BPC 157 (all regimens) fully counteracted the perilous disease course from the very beginning (i.e., with the BPC 157 bath, blood vessels remained present at the gastric surface after anastomosis creation) and eliminated mortality. Additionally, BPC 157 treatment in combination with L-NAME nullified any effect of L-NAME that otherwise intensified the regular course. Consistently, with worsening (with L-NAME administration) and amelioration (with L-arginine), either L-arginine amelioration prevails (attenuated esophageal and gastric lesions) or they counteract each other (L-NAME + L-arginine); with the addition of BPC 157 (L-NAME + L-arginine + BPC 157), there was a marked beneficial effect. BPC 157 treatment for esophagogastric anastomosis, along with NOS-blocker L-NAME and/or NOS substrate L-arginine, demonstrated an innate NO-system disability (as observed with L-arginine effectiveness). BPC 157 distinctively affected corresponding events: worsening (obtained with L-NAME administration that was counteracted); or amelioration (L-arginine + BPC 157-rats correspond to BPC 157-rats).
CONCLUSION Innate NO-system disability for esophagogastric anastomoses, including L-NAME-worsening, suggests that these effects could be corrected by L-arginine and almost completely eliminated by BPC 157 therapy.
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Lojo N, Rasic Z, Zenko Sever A, Kolenc D, Vukusic D, Drmic D, Zoricic I, Sever M, Seiwerth S, Sikiric P. Effects of Diclofenac, L-NAME, L-Arginine, and Pentadecapeptide BPC 157 on Gastrointestinal, Liver, and Brain Lesions, Failed Anastomosis, and Intestinal Adaptation Deterioration in 24 Hour-Short-Bowel Rats. PLoS One 2016; 11:e0162590. [PMID: 27627764 PMCID: PMC5023193 DOI: 10.1371/journal.pone.0162590] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2015] [Accepted: 08/25/2016] [Indexed: 12/11/2022] Open
Abstract
Stable gastric pentadecapeptide BPC 157 was previously used to ameliorate wound healing following major surgery and counteract diclofenac toxicity. To resolve the increasing early risks following major massive small bowel resectioning surgery, diclofenac combined with nitric oxide (NO) system blockade was used, suggesting therapy with BPC 157 and the nitric oxide synthase (NOS substrate) L-arginine, is efficacious. Immediately after anastomosis creation, short-bowel rats were untreated or administered intraperitoneal diclofenac (12 mg/kg), BPC 157 (10 μg/kg or 10 ng/kg), L-NG-nitroarginine methyl ester (L-NAME, 5 mg/kg), L-arginine (100 mg/kg) alone or combined, and assessed 24 h later. Short-bowel rats exhibited poor anastomosis healing, failed intestine adaptation, and gastrointestinal, liver, and brain lesions, which worsened with diclofenac. This was gradually ameliorated by immediate therapy with BPC 157 and L-arginine. Contrastingly, NOS-blocker L-NAME induced further aggravation and lesions gradually worsened. Specifically, rats with surgery alone exhibited mild stomach/duodenum lesions, considerable liver lesions, and severe cerebral/hippocampal lesions while those also administered diclofenac showed widespread severe lesions in the gastrointestinal tract, liver, cerebellar nuclear/Purkinje cells, and cerebrum/hippocampus. Rats subjected to surgery, diclofenac, and L-NAME exhibited the mentioned lesions, worsening anastomosis, and macro/microscopical necrosis. Thus, rats subjected to surgery alone showed evidence of deterioration. Furtheremore, rats subjected to surgery and administered diclofenac showed worse symptoms, than the rats subjected to surgery alone did. Rats subjected to surgery combined with diclofenac and L-NAME showed the worst deterioration. Rats subjected to surgery exhibited habitual adaptation of the remaining small intestine, which was markedly reversed in rats subjected to surgery and diclofenac, and those with surgery, diclofenac, and L-NAME. BPC 157 completely ameliorated symptoms in massive intestinal resection-, massive intestinal resection plus diclofenac-, and massive intestinal resection plus diclofenac plus L-NAME-treated short bowel rats that presented with cyclooxygenase (COX)-NO-system inhibition. L-arginine ameliorated only L-NAME-induced aggravation of symptoms in rats subjected to massive intestinal resection and administered diclofenac plus L-NAME.
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Affiliation(s)
- Nermin Lojo
- Department of Pharmacology, School of Medicine, University of Zagreb, POB 916, Salata 11, 10000 Zagreb, Croatia
| | - Zarko Rasic
- Department of Pharmacology, School of Medicine, University of Zagreb, POB 916, Salata 11, 10000 Zagreb, Croatia
| | - Anita Zenko Sever
- Department of Pathology, School of Medicine, University of Zagreb, Salata 9, 10000 Zagreb, Croatia
| | - Danijela Kolenc
- Department of Pathology, School of Medicine, University of Zagreb, Salata 9, 10000 Zagreb, Croatia
| | - Darko Vukusic
- Department of Pharmacology, School of Medicine, University of Zagreb, POB 916, Salata 11, 10000 Zagreb, Croatia
| | - Domagoj Drmic
- Department of Pharmacology, School of Medicine, University of Zagreb, POB 916, Salata 11, 10000 Zagreb, Croatia
| | - Ivan Zoricic
- Department of Pharmacology, School of Medicine, University of Zagreb, POB 916, Salata 11, 10000 Zagreb, Croatia
| | - Marko Sever
- Department of Pharmacology, School of Medicine, University of Zagreb, POB 916, Salata 11, 10000 Zagreb, Croatia
| | - Sven Seiwerth
- Department of Pathology, School of Medicine, University of Zagreb, Salata 9, 10000 Zagreb, Croatia
| | - Predrag Sikiric
- Department of Pharmacology, School of Medicine, University of Zagreb, POB 916, Salata 11, 10000 Zagreb, Croatia
- * E-mail:
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Stambolija V, Stambolija TP, Holjevac JK, Murselovic T, Radonic J, Duzel V, Duplancic B, Uzun S, Zivanovic-Posilovic G, Kolenc D, Drmic D, Romic Z, Seiwerth S, Sikiric P. BPC 157: The counteraction of succinylcholine, hyperkalemia, and arrhythmias. Eur J Pharmacol 2016; 781:83-91. [PMID: 27060013 DOI: 10.1016/j.ejphar.2016.04.004] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2016] [Revised: 03/31/2016] [Accepted: 04/04/2016] [Indexed: 12/13/2022]
Abstract
After the demonstration of its life-saving effect in severe hyperkalemia and the recovery of skeletal muscle after injury, pentadecapeptide BPC 157 has been shown to attenuate the local paralytic effect induced by succinylcholine, in addition to systemic muscle disability (and consequent muscle damage). Hyperkalemia, arrhythmias and a rise in serum enzyme values, were counteracted in rats. Assessments were made at 3 and 30min and 1, 3, 5, and 7 days after succinylcholine administration (1.0mg/kg into the right anterior tibial muscle). BPC 157 (10µg/kg, 10ng/kg) (given intraperitoneally 30min before or immediately after succinylcholine or per-orally in drinking water through 24h until succinylcholine administration) mitigated both local and systemic disturbances. BPC 157 completely eliminated hyperkalemia and arrhythmias, markedly attenuated or erradicated behavioral agitation, muscle twitches, motionless resting and completely eliminated post-succinylcholine hyperalgesia. BPC 157 immediately eliminated leg contractures and counteracted both edema and the decrease in muscle fibers in the diaphragm and injected/non-injected anterior tibial muscles. Therefore, the depolarizing neuromuscular blocker effects of succinylcholine were successfully antagonized.
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Affiliation(s)
- Vasilije Stambolija
- Department of Pharmacology, School of Medicine, University of Zagreb, Zagreb, Croatia
| | | | | | - Tamara Murselovic
- Department of Pharmacology, School of Medicine, University of Zagreb, Zagreb, Croatia
| | - Jelena Radonic
- Department of Pharmacology, School of Medicine, University of Zagreb, Zagreb, Croatia
| | - Viktor Duzel
- Department of Pharmacology, School of Medicine, University of Zagreb, Zagreb, Croatia
| | - Bozidar Duplancic
- Department of Pharmacology, School of Medicine, University of Zagreb, Zagreb, Croatia
| | - Sandra Uzun
- Department of Pharmacology, School of Medicine, University of Zagreb, Zagreb, Croatia
| | | | - Danijela Kolenc
- Department of Pathology, School of Medicine, University of Zagreb, Zagreb, Croatia
| | - Domagoj Drmic
- Department of Pharmacology, School of Medicine, University of Zagreb, Zagreb, Croatia
| | - Zeljko Romic
- Department of Pharmacology, School of Medicine, University of Zagreb, Zagreb, Croatia
| | - Sven Seiwerth
- Department of Pathology, School of Medicine, University of Zagreb, Zagreb, Croatia
| | - Predrag Sikiric
- Department of Pharmacology, School of Medicine, University of Zagreb, Zagreb, Croatia.
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Grgic T, Grgic D, Drmic D, Sever AZ, Petrovic I, Sucic M, Kokot A, Klicek R, Sever M, Seiwerth S, Sikiric P. Stable gastric pentadecapeptide BPC 157 heals rat colovesical fistula. Eur J Pharmacol 2016; 780:1-7. [PMID: 26875638 DOI: 10.1016/j.ejphar.2016.02.038] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2015] [Revised: 02/09/2016] [Accepted: 02/10/2016] [Indexed: 02/07/2023]
Abstract
To establish the effects of BPC 157 on the healing of rat colovesical fistulas, Wistar Albino male rats were randomly assigned to different groups. BPC 157, a stable gastric pentadecapeptide, has been used in clinical applications-specifically, in ulcerative colitis-and was successful in treating both external and internal fistulas. BPC 157 was provided daily, perorally, in drinking water (10µg/kg, 12ml/rat/day) until sacrifice or, alternatively, 10µg/kg or 10ng/kg intraperitoneally, with the first application at 30min after surgery and the last at 24h before sacrifice. Controls simultaneously received an equivolume of saline (5.0ml/kg ip) or water only (12ml/rat/day). Assessment (i.e., colon and vesical defects, fistula leaking, fecaluria and defecation through the fistula, adhesions and intestinal obstruction as healing processes) took place on days 7, 14 and 28. Control colovesical fistulas regularly exhibited poor healing, with both of the defects persisting; continuous fistula leakage; fecaluria and defecation through the fistula; advanced adhesion formation; and intestinal obstruction. By contrast, BPC 157 given perorally or intraperitoneally and in µg- and ng-regimens rapidly improved the whole presentation, with both colon and vesical defects simultaneously ameliorated and eventually healed. The maximal instilled volume was continuously raised until it reached the values of healthy rats, there were no signs of fecaluria and no defecation through the fistula, there was counteraction of advanced adhesion formation or there was an intestinal obstruction. In conclusion, BPC 157 effects appear to be suited to inducing full healing of colocutaneous fistulas in rats.
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Affiliation(s)
- Tihomir Grgic
- Department of Pharmacology, School of Medicine, University of Zagreb, POB 916, Salata 11, 10000 Zagreb, Croatia
| | - Dora Grgic
- Department of Pharmacology, School of Medicine, University of Zagreb, POB 916, Salata 11, 10000 Zagreb, Croatia
| | - Domagoj Drmic
- Department of Pharmacology, School of Medicine, University of Zagreb, POB 916, Salata 11, 10000 Zagreb, Croatia
| | - Anita Zenko Sever
- Department of Pathology, School of Medicine, University of Zagreb, Salata 9, 10000 Zagreb, Croatia
| | - Igor Petrovic
- Department of Pharmacology, School of Medicine, University of Zagreb, POB 916, Salata 11, 10000 Zagreb, Croatia
| | - Mario Sucic
- Department of Pharmacology, School of Medicine, University of Zagreb, POB 916, Salata 11, 10000 Zagreb, Croatia
| | - Antonio Kokot
- Department of Anatomy and Neuroscience, Faculty of Medicine, J.J. Strossmayer University of Osijek, J. Huttlera 4, 31000 Osijek, Croatia
| | - Robert Klicek
- Department of Pharmacology, School of Medicine, University of Zagreb, POB 916, Salata 11, 10000 Zagreb, Croatia
| | - Marko Sever
- Department of Pharmacology, School of Medicine, University of Zagreb, POB 916, Salata 11, 10000 Zagreb, Croatia
| | - Sven Seiwerth
- Department of Pathology, School of Medicine, University of Zagreb, Salata 9, 10000 Zagreb, Croatia
| | - Predrag Sikiric
- Department of Pharmacology, School of Medicine, University of Zagreb, POB 916, Salata 11, 10000 Zagreb, Croatia.
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Stable gastric pentadecapeptide BPC 157 heals rectovaginal fistula in rats. Life Sci 2016; 148:63-70. [PMID: 26872976 DOI: 10.1016/j.lfs.2016.02.029] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2015] [Revised: 01/22/2016] [Accepted: 02/08/2016] [Indexed: 02/07/2023]
Abstract
AIM Rectovaginal fistula is a devastating condition providing more than 99% of patients for surgical treatment. We hypothesized that rectovaginal fistula may be healed by therapy with stable gastric pentadecapeptide BPC 157, in consistence with its initial clinical application and effect on external fistulas. MAIN METHODS BPC 157 (10μg/kg or 10ng/kg) was given perorally, in drinking water (0.16μg/ml or 0.16ng/ml, 12ml/rat/day) till sacrifice, or alternatively, intraperitoneally, first application at 30min after surgery, last at 24h before sacrifice. Controls simultaneously received an equivolume of saline (5.0ml/kg ip) or water only (12ml/rat/day). The assessment (i.e., rectal and vaginal defect, fistula leakage, defecation through the fistula, adhesions and intestinal obstruction as healing processes) was at day 1, 3, 5, 7, 10, 14 and 21. KEY FINDINGS Regularly, rectovaginal fistulas exhibited poor healing, with both of the defects persisting, continuous fistula leakage, defecation through the fistula, advanced adhesion formation and intestinal obstruction. By contrast, BPC 157 given perorally or intraperitoneally, in μg- and ng-regimens rapidly improved the whole presentation, with both rectal and vaginal defects simultaneously ameliorated and eventually healed. The maximal instilled volume was continuously raised till the values of healthy rats were achieved, there were no signs of defecation through the fistula. A counteraction of advanced adhesion formation and intestinal obstruction was achieved. Microscopic improvement was along with macroscopic findings. SIGNIFICANCE BPC 157 effects appear to be suited to induce a full healing of rectovaginal fistulas in rats.
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Kokot A, Zlatar M, Stupnisek M, Drmic D, Radic R, Vcev A, Seiwerth S, Sikiric P. NO system dependence of atropine-induced mydriasis and L-NAME- and L-arginine-induced miosis: Reversal by the pentadecapeptide BPC 157 in rats and guinea pigs. Eur J Pharmacol 2015; 771:211-9. [PMID: 26698393 DOI: 10.1016/j.ejphar.2015.12.016] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2015] [Revised: 11/13/2015] [Accepted: 12/09/2015] [Indexed: 02/07/2023]
Abstract
We revealed an immediate and hours-lasting particular NO-specific parallel miotic effect of L-NAME and L-arginine in rats and guinea pigs and a stable gastric pentadecapeptide BPC 157 157-particular effect vs. that of atropine-induced mydriasis while examining the NO system role in the normal pupils responses and pupils with atropine-induced mydriasis. We also assessed the responses to BPC 157 and its possible modulation of the changes caused by L-NAME/L-arginine and atropine. We administered locally (two drops/eye) or systemically (intraperitoneally/kg) [BPC 157 (0.4µg/eye; 10µg, 10ng, 10pg/kg), L-NAME (0.1mg/eye; 5mg/kg), and L-arginine (2mg/eye; 100mg/kg) alone and combined] at 3min prior to assessment (normal pupils) or alternatively at maximal 1% atropine-induced mydriasis (30min after two drops were administered to each eye). L-NAME/L-arginine. Normal pupil. L-NAME-miosis and L-arginine-miosis shortened and attenuated each other's responses when combined (L-NAME+L-arginine) (except with guinea pigs treated locally) and were thereby NO-specific. Atropine-pupil. Both L-NAME and L-arginine counteracted atropine-induced mydriasis. With few exceptions, the atropine+L-NAME+L-arginine-animals showed a consistent shift toward the left. BPC 157. Normal pupil. Always, BPC 157 alone (both species; locally; systemically; all regimens) did not affect normal pupils. Despite specific exceptions, BPC 157 distinctively affects L-arginine-miosis (prolongation) and L-NAME-miosis (shortening). When L-arginine and L-NAME were combined (L-NAME+L-arginine+BPC 157), the effect was less pronounced. Atropine-pupil. BPC 157 alone counteracted atropine-induced mydriasis. With few exceptions (when administered with L-NAME or L-arginine or L-NAME+L-arginine), BPC 157 augments their counteracting effects. Thus, along with its l-NAME/L-arginine effects, BPC 157 participates in ocular control, potentially via NO-mediated and cholinergic mechanisms.
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Affiliation(s)
- Antonio Kokot
- Department of Anatomy and Neuroscience, Faculty of Medicine, J.J. Strossmayer University of Osijek, J.Huttlera 4, 31000 Osijek, Croatia
| | - Mirna Zlatar
- Department of Pharmacology, School of Medicine, University of Zagreb, POB 916, Salata 11, 10000 Zagreb, Croatia
| | - Mirjana Stupnisek
- Department of Pharmacology, Faculty of Medicine, J.J. Strossmayer University of Osijek, J.Huttlera 4, 31000 Osijek, Croatia
| | - Domagoj Drmic
- Department of Pharmacology, School of Medicine, University of Zagreb, POB 916, Salata 11, 10000 Zagreb, Croatia
| | - Radivoje Radic
- Department of Anatomy and Neuroscience, Faculty of Medicine, J.J. Strossmayer University of Osijek, J.Huttlera 4, 31000 Osijek, Croatia
| | - Aleksandar Vcev
- Department of Pharmacology, School of Medicine, University of Zagreb, POB 916, Salata 11, 10000 Zagreb, Croatia
| | - Sven Seiwerth
- Department of Pathology, School of Medicine, University of Zagreb, Salata 9, 10000 Zagreb, Croatia
| | - Predrag Sikiric
- Department of Pharmacology, School of Medicine, University of Zagreb, POB 916, Salata 11, 10000 Zagreb, Croatia.
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Zemba M, Cilic AZ, Balenovic I, Cilic M, Radic B, Suran J, Drmic D, Kokot A, Stambolija V, Murselovic T, Holjevac JK, Uzun S, Djuzel V, Vlainic J, Seiwerth S, Sikiric P. BPC 157 antagonized the general anaesthetic potency of thiopental and reduced prolongation of anaesthesia induced by L-NAME/thiopental combination. Inflammopharmacology 2015; 23:329-36. [PMID: 26563892 DOI: 10.1007/s10787-015-0249-9] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2015] [Accepted: 09/28/2015] [Indexed: 02/06/2023]
Abstract
AIM We hypothesized that certain effects of the general anaesthetic thiopental are dependent on NO-related mechanisms, which were consequently counteracted by stable gastric pentadecapeptide BPC 157. MAIN METHODS (1) All rats intraperitoneally received thiopental (20, 30, 40, and 50 mg/kg) while medication BPC 157 (10 μg/kg, 10 ng/kg, and 10 pg/kg) was given intraperitoneally at 5 min before thiopental. (2) To determine NO-related mechanisms, all rats received intraperitoneally thiopental 40 mg/kg while BPC 157 (10 μg/kg), L-NAME (10 mg/kg) and L-arginine (30 mg/kg) were applied alone and/or combined. BPC 157 was given at 25 min before thiopental while L-NAME, L-arginine, alone and/or combined, were applied at 20 min before thiopental. KEY FINDINGS (1) BPC 157 own effect on thiopental anaesthesia: BPC 157 (10 ng/kg and 10 μg/kg) caused a significant antagonism of general anaesthesia produced by thiopental with a parallel shift of the dose-response curve to the right. (2) L-NAME-L-arginine-BPC 157 interrelations: L-NAME: Thiopental-induced anaesthesia duration was tripled. L-arginine: Usual thiopental anaesthesia time was not influenced. Active only when given with L-NAME or BPC 157: potentiating effects of L-NAME were lessened, not abolished; shortening effect of BPC 157: abolished. BPC 157 and L-NAME: Potentiating effects of L-NAME were abolished. BPC 157 and L-NAME and L-arginine: BPC 157 +L-NAME +L-arginine rats exhibited values close to those in BPC 157 rats. SIGNIFICANCE Thiopental general anaesthesia is simultaneously manipulated in both ways with NO system activity modulation, L-NAME (prolongation) and BPC 157 (shortening/counteraction) and L-arginine (interference with L-NAME and BPC 157).
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Affiliation(s)
- Mladen Zemba
- Department of Pharmacology, School of Medicine, University of Zagreb, Salata 11, PO Box 916, 10000, Zagreb, Croatia
| | - Andrea Zemba Cilic
- Department of Pharmacology, School of Medicine, University of Zagreb, Salata 11, PO Box 916, 10000, Zagreb, Croatia
| | - Igor Balenovic
- Department of Pharmacology, School of Medicine, University of Zagreb, Salata 11, PO Box 916, 10000, Zagreb, Croatia
| | - Matija Cilic
- Department of Pharmacology, School of Medicine, University of Zagreb, Salata 11, PO Box 916, 10000, Zagreb, Croatia
| | - Bozo Radic
- Department of Pharmacology, School of Medicine, University of Zagreb, Salata 11, PO Box 916, 10000, Zagreb, Croatia
| | - Jelena Suran
- Department of Pharmacology, School of Medicine, University of Zagreb, Salata 11, PO Box 916, 10000, Zagreb, Croatia
| | - Domagoj Drmic
- Department of Pharmacology, School of Medicine, University of Zagreb, Salata 11, PO Box 916, 10000, Zagreb, Croatia
| | - Antonio Kokot
- Department of Pharmacology, School of Medicine, University of Zagreb, Salata 11, PO Box 916, 10000, Zagreb, Croatia
| | - Vasilije Stambolija
- Department of Pharmacology, School of Medicine, University of Zagreb, Salata 11, PO Box 916, 10000, Zagreb, Croatia
| | - Tamara Murselovic
- Department of Pharmacology, School of Medicine, University of Zagreb, Salata 11, PO Box 916, 10000, Zagreb, Croatia
| | - Jadranka Katancic Holjevac
- Department of Pharmacology, School of Medicine, University of Zagreb, Salata 11, PO Box 916, 10000, Zagreb, Croatia
| | - Sandra Uzun
- Department of Pharmacology, School of Medicine, University of Zagreb, Salata 11, PO Box 916, 10000, Zagreb, Croatia
| | - Viktor Djuzel
- Department of Pharmacology, School of Medicine, University of Zagreb, Salata 11, PO Box 916, 10000, Zagreb, Croatia
| | - Josipa Vlainic
- Department of Pharmacology, School of Medicine, University of Zagreb, Salata 11, PO Box 916, 10000, Zagreb, Croatia
| | - Sven Seiwerth
- Department of Pathology, School of Medicine, University of Zagreb, Zagreb, Croatia
| | - Predrag Sikiric
- Department of Pharmacology, School of Medicine, University of Zagreb, Salata 11, PO Box 916, 10000, Zagreb, Croatia.
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Masnec S, Kokot A, Zlatar M, Kalauz M, Kunjko K, Radic B, Klicek R, Drmic D, Lazic R, Brcic L, Radic R, Ivekovic R, Seiwerth S, Sikiric P. Perforating corneal injury in rat and pentadecapeptide BPC 157. Exp Eye Res 2015; 136:9-15. [PMID: 25912999 DOI: 10.1016/j.exer.2015.04.016] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2014] [Revised: 04/09/2015] [Accepted: 04/22/2015] [Indexed: 12/12/2022]
Abstract
Based on its healing effects in various tissues, we hypothesized that the stable gastric pentadecapeptide BPC 157 heals corneal ulcerations in rats and effects corneal transparency. We made a penetrant linear 2-mm incision in the paralimbal region of the left cornea at the 5 o'clock position with a 20-gauge MVR incision knife at 45° under an operating microscope. Medication was BPC 157 (2 pg/mL, 2 ng/mL, and 2 μg/mL distilled water, two eye drops/left rat eye) immediately after injury induction and then every 8 h up to 120 h; controls received an equal volume of distilled water. In contrast to the poor healing response in controls, BPC 157 significantly accelerated the healing process in 2 μg and 2 ng BPC 157-treated eyes, starting 24 h after the injury, and the fluorescein and Seidel tests became negative. The epithelial defects were completely healed at 72 h (2 μg BPC 157-treated group) and at 96 h (2 ng BPC 157-treated group) after injury. Aqueous cells were absent at 96 h and 120 h after injury in the 2 μg and 2 ng BPC 157-treated groups, respectively. In conclusion, BPC 157 effects the rapid regaining of corneal transparency. Whereas controls developed new vessels that grew from the limbus to the penetrated area, BPC 157-treated rats generally had no new vessels, and those that did form in the limbus did not make contact with the penetrated area. Thus, BPC 157 eye drops successfully close perforating corneal incisions in rats.
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Affiliation(s)
- Sanja Masnec
- University Department of Ophthalmology, Zagreb University Hospital Center, Zagreb, Croatia
| | - Antonio Kokot
- Department of Anatomy and Neuroscience, School of Medicine, University of Osijek, Osijek, Croatia
| | - Mirna Zlatar
- Department of Pharmacology, School of Medicine, University of Zagreb, Zagreb, Croatia
| | - Miro Kalauz
- University Department of Ophthalmology, Zagreb University Hospital Center, Zagreb, Croatia
| | - Kristian Kunjko
- Department of Pharmacology, School of Medicine, University of Zagreb, Zagreb, Croatia
| | - Bozo Radic
- Department of Pharmacology, School of Medicine, University of Zagreb, Zagreb, Croatia
| | - Robert Klicek
- Department of Pharmacology, School of Medicine, University of Zagreb, Zagreb, Croatia
| | - Domagoj Drmic
- Department of Pharmacology, School of Medicine, University of Zagreb, Zagreb, Croatia
| | - Ratimir Lazic
- Department of Pharmacology, School of Medicine, University of Zagreb, Zagreb, Croatia
| | - Luka Brcic
- Department of Pathology, School of Medicine, University of Zagreb, Zagreb, Croatia
| | - Radivoje Radic
- Department of Anatomy and Neuroscience, School of Medicine, University of Osijek, Osijek, Croatia
| | - Renata Ivekovic
- University Department of Ophthalmology, Sestre Milosrdnice University Hospital Center, Zagreb, Croatia
| | - Sven Seiwerth
- Department of Pathology, School of Medicine, University of Zagreb, Zagreb, Croatia
| | - Predrag Sikiric
- Department of Pharmacology, School of Medicine, University of Zagreb, Zagreb, Croatia.
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Huang T, Zhang K, Sun L, Xue X, Zhang C, Shu Z, Mu N, Gu J, Zhang W, Wang Y, Zhang Y, Zhang W. Body protective compound-157 enhances alkali-burn wound healing in vivo and promotes proliferation, migration, and angiogenesis in vitro. DRUG DESIGN DEVELOPMENT AND THERAPY 2015; 9:2485-99. [PMID: 25995620 PMCID: PMC4425239 DOI: 10.2147/dddt.s82030] [Citation(s) in RCA: 58] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Chemical burns take up a high proportion of burns admissions and can penetrate deep into tissues. Various reagents have been applied in the treatment of skin chemical burns; however, no optimal reagent for skin chemical burns currently exists. The present study investigated the effect of topical body protective compound (BPC)-157 treatment on skin wound healing, using an alkali burn rat model. Topical treatment with BPC-157 was shown to accelerate wound closure following an alkali burn. Histological examination of skin sections with hematoxylin–eosin and Masson staining showed better granulation tissue formation, reepithelialization, dermal remodeling, and a higher extent of collagen deposition when compared to the model control group on the 18th day postwounding. BPC-157 could promote vascular endothelial growth factor expression in wounded skin tissues. Furthermore, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and cell cycle analysis demonstrated that BPC-157 enhanced the proliferation of human umbilical vein endothelial cells (HUVECs). Transwell assay and wound healing assay showed that BPC-157 significantly promoted migration of HUVECs. We also observed that BPC-157 upregulated the expression of VEGF-a and accelerated vascular tube formation in vitro. Moreover, further studies suggested that BPC-157 regulated the phosphorylation level of extracellular signal-regulated kinases 1 and 2 (ERK1/2) as well as its downstream targets, including c-Fos, c-Jun, and Egr-1, which are key molecules involved in cell growth, migration, and angiogenesis. Altogether, our results indicated that BPC-157 treatment may accelerate wound healing in a model of alkali burn-induced skin injury. The therapeutic mechanism may be associated with accelerated granulation tissue formation, reepithelialization, dermal remodeling, and collagen deposition through ERK1/2 signaling pathway.
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Affiliation(s)
- Tonglie Huang
- State Key Laboratory of Cancer Biology, Department of Biopharmaceutics, School of Pharmacy, The Fourth Military Medical University, Xi'an, People's Republic of China
| | - Kuo Zhang
- National Engineering Research Center for Miniaturized Detection Systems, School of Life Sciences, Northwest University, Xi'an, People's Republic of China
| | - Lijuan Sun
- Department of Ophthalmology, Xijing Hospital, The Fourth Military Medical University, Xi'an, People's Republic of China
| | - Xiaochang Xue
- State Key Laboratory of Cancer Biology, Department of Biopharmaceutics, School of Pharmacy, The Fourth Military Medical University, Xi'an, People's Republic of China
| | - Cun Zhang
- State Key Laboratory of Cancer Biology, Department of Biopharmaceutics, School of Pharmacy, The Fourth Military Medical University, Xi'an, People's Republic of China
| | - Zhen Shu
- State Key Laboratory of Cancer Biology, Department of Biopharmaceutics, School of Pharmacy, The Fourth Military Medical University, Xi'an, People's Republic of China
| | - Nan Mu
- State Key Laboratory of Cancer Biology, Department of Biopharmaceutics, School of Pharmacy, The Fourth Military Medical University, Xi'an, People's Republic of China
| | - Jintao Gu
- State Key Laboratory of Cancer Biology, Department of Biopharmaceutics, School of Pharmacy, The Fourth Military Medical University, Xi'an, People's Republic of China
| | - Wangqian Zhang
- State Key Laboratory of Cancer Biology, Department of Biopharmaceutics, School of Pharmacy, The Fourth Military Medical University, Xi'an, People's Republic of China
| | - Yukun Wang
- State Key Laboratory of Cancer Biology, Department of Biopharmaceutics, School of Pharmacy, The Fourth Military Medical University, Xi'an, People's Republic of China
| | - Yingqi Zhang
- State Key Laboratory of Cancer Biology, Department of Biopharmaceutics, School of Pharmacy, The Fourth Military Medical University, Xi'an, People's Republic of China
| | - Wei Zhang
- State Key Laboratory of Cancer Biology, Department of Biopharmaceutics, School of Pharmacy, The Fourth Military Medical University, Xi'an, People's Republic of China
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Stupnisek M, Kokot A, Drmic D, Hrelec Patrlj M, Zenko Sever A, Kolenc D, Radic B, Suran J, Bojic D, Vcev A, Seiwerth S, Sikiric P. Pentadecapeptide BPC 157 Reduces Bleeding and Thrombocytopenia after Amputation in Rats Treated with Heparin, Warfarin, L-NAME and L-Arginine. PLoS One 2015; 10:e0123454. [PMID: 25897838 PMCID: PMC4405609 DOI: 10.1371/journal.pone.0123454] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2014] [Accepted: 03/03/2015] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND BPC 157 is a stable gastric pentadecapeptide recently implicated with a role in hemostasis. While NO is largely implicated in hemostatic mechanisms, in tail-amputation-models under heparin- and warfarin-administration, both the NO-synthase (NOS)-blocker, L-NAME (prothrombotic) and the NOS-substrate L-arginine (antithrombotic), were little investigated. Objective. To investigate the effect of L-NAME and L-arginine on hemostatic parameters, and to reveal the effects of BPC 157 on the L-NAME- and L-arginine-induced hemostatic actions under different pathological condition: tail amputation without or with anticoagulants, heparin or warfarin. METHODS Tail amputation, and/or i.v.-heparin (10 mg/kg), i.g.-warfarin (1.5 mg/kg/day for 3 days) were used in rats. Treatment includes BPC 157, L-NAME, L-arginine, per se and their combination. RESULTS After (tail) amputation, with or without i.v.-heparin or i.g.-warfarin, BPC 157 (10 μg/kg, 10 ng/kg, i.p., i.v. (heparin), 10 μg/kg i.g. (warfarin)) always reduced bleeding time and/or haemorrhage and counteracted thrombocytopenia. As for L-NAME and/or L-arginine, we noted: L-arginine (100 mg/kg i.p.)-rats: more bleeding, less/no thrombocytopenia; L-NAME (5 mg/kg i.p.)-rats: less bleeding (amputation only), but present thrombocytopenia; L-NAME+L-arginine-rats also exhibited thrombocytopenia: L-NAME counteracted L-arginine-increased bleeding, L-arginine did not counteract L-NAME-thrombocytopenia. All animals receiving BPC 157 in addition (BPC 157 μg+L-NAME; BPC 157 μg+L-arginine, BPC 157 μg+L-NAME+L-arginine), exhibited decreased haemorrhage and markedly counteracted thrombocytopenia. CONCLUSIONS L-NAME (thrombocytopenia), L-arginine (increased haemorrhage) counteraction and BPC 157 (decreased haemorrhage, counteracted thrombocytopenia) with rescue against two different anticoagulants, implicate a BPC 157 modulatory and balancing role with rescued NO-hemostatic mechanisms.
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Affiliation(s)
- Mirjana Stupnisek
- Faculty of Medicine, J.J. Strossmayer University of Osijek, Osijek, Croatia
| | - Antonio Kokot
- Faculty of Medicine, J.J. Strossmayer University of Osijek, Osijek, Croatia
| | - Domagoj Drmic
- Department of Pharmacology, School of Medicine, University of Zagreb, Zagreb, Croatia
| | - Masa Hrelec Patrlj
- Department of Pharmacology, School of Medicine, University of Zagreb, Zagreb, Croatia
| | - Anita Zenko Sever
- Department of Pathology, School of Medicine, University of Zagreb, Zagreb, Croatia
| | - Danijela Kolenc
- Department of Pathology, School of Medicine, University of Zagreb, Zagreb, Croatia
| | - Bozo Radic
- Department of Pharmacology, School of Medicine, University of Zagreb, Zagreb, Croatia
| | - Jelena Suran
- Department of Pharmacology, School of Medicine, University of Zagreb, Zagreb, Croatia
| | - Davor Bojic
- Department of Pharmacology, School of Medicine, University of Zagreb, Zagreb, Croatia
| | - Aleksandar Vcev
- Faculty of Medicine, J.J. Strossmayer University of Osijek, Osijek, Croatia
| | - Sven Seiwerth
- Department of Pathology, School of Medicine, University of Zagreb, Zagreb, Croatia
| | - Predrag Sikiric
- Department of Pharmacology, School of Medicine, University of Zagreb, Zagreb, Croatia
- * E-mail:
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47
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Jandric I, Vrcic H, Jandric Balen M, Kolenc D, Brcic L, Radic B, Drmic D, Seiwerth S, Sikiric P. Salutary effect of gastric pentadecapeptide BPC 157 in two different stress urinary incontinence models in female rats. Med Sci Monit Basic Res 2013; 19:93-102. [PMID: 23478678 PMCID: PMC3940704 DOI: 10.12659/msmbr.883828] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
Background Since an originally anti-ulcer stable gastric pentadecapeptide BPC 157 (PL 14736) was shown to promote healing of injured striated muscle and smooth muscle in the gastrointestinal tract, we explored its therapeutic potentials for leak point pressure (LPP) recovery in rat stress urinary incontinence (SUI) after transabdominal urethrolysis (TU) and prolonged vaginal dilatation (VD). Material/Methods During a 7-day period, TU-rats and VD-rats (or healthy rats) received BPC 157, either (i) intraperitoneally, 10 μg/kg or 10 ng/kg, once daily (first administration 30 min after surgery, last 24 h before LPP-testing and sacrifice), or (ii) per-orally, 10 μg/kg in drinking water (0.16 μg/mL, 12 mL/rat/day). Vesicourethral segments were harvested for immunohistochemical evaluation. Results All BPC 157 regimens counteracted decrease of LPP values in TU-rats and VD-rats. Additionally, BPC 157-TU rats (μg-intraperitoneally or per-orally) and BPC 157-VD rats (μg intraperitoneally) reached LPP values originally noted in healthy rats. Conversely, in healthy rats, BPC 157 did not alter LPP. Immunohistochemical studies revealed higher desmin (delineates striated organization of skeletal muscle), smooth muscle actin, and CD34 (angiogenic marker) positivity within the urethral wall in BPC 157-treated rats vs. controls, as well as overall preserved muscle/connective tissue ratio assessed with Mallory’s trichrome staining. Conclusions Pentadecapeptide BPC 157, applied parenterally or per-orally, appears to ameliorate the SUI in rat models, improving the otherwise detrimental course of healing after VD and TU, which may be analogous to human injury. These beneficial effects may possibly be selectively used in future strategies for treatment of SUI.
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Affiliation(s)
- Ivan Jandric
- General Hospital "Dr. Josip Bencevic", Slavonski Brod, Croatia
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Barisic I, Balenovic D, Klicek R, Radic B, Nikitovic B, Drmic D, Udovicic M, Strinic D, Bardak D, Berkopic L, Djuzel V, Sever M, Cvjetko I, Romic Z, Sindic A, Bencic ML, Seiwerth S, Sikiric P. Mortal hyperkalemia disturbances in rats are NO-system related. The life saving effect of pentadecapeptide BPC 157. ACTA ACUST UNITED AC 2013; 181:50-66. [PMID: 23327997 DOI: 10.1016/j.regpep.2012.12.007] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2012] [Revised: 11/23/2012] [Accepted: 12/17/2012] [Indexed: 02/07/2023]
Abstract
We demonstrate the full counteracting ability of stable gastric pentadecapeptide BPC 157 against KCl-overdose (intraperitoneal (i), intragastric (ii), in vitro (iii)), NO-system related. (i) We demonstrated potential (/kg) of: BPC 157 (10ng, 10μg ip, complete counteraction), l-arginine (100mg ip, attenuation) vs. L-NAME (5mg ip, deadly aggravation), given alone and/or combined, before or after intraperitoneal KCl-solution application (9mEq/kg). Therapy was confronted with promptly unrelenting hyperkalemia (>12mmol/L), arrhythmias (and muscular weakness, hypertension, low pressure in lower esophageal and pyloric sphincter) with an ultimate and a regularly inevitable lethal outcome within 30min. Previously, we established BPC 157-NO-system interaction; now, a huge life-saving potential. Given 30min before KCl, all BPC 157 regimens regained sinus rhythm, had less prolongation of QRS, and had no asystolic pause. BPC 157 therapy, given 10min after KCl-application, starts the rescue within 5-10min, completely restoring normal sinus rhythm at 1h. Likewise, other hyperkalemia-disturbances (muscular weakness, hypertension, low sphincteric pressure) were also counteracted. Accordingly with NO-system relation, deadly aggravation by L-NAME: l-arginine brings the values to the control levels while BPC 157 always completely nullified lesions, markedly below those of controls. Combined with l-arginine, BPC 157 exhibited no additive effect. (ii) Intragastric KCl-solution application (27mEq/kg) - (hyperkalemia 7mmol/L): severe stomach mucosal lesions, sphincter failure and peaked T waves were fully counteracted by intragastric BPC 157 (10ng, 10μg) application, given 30min before or 10min after KCl. (iii). In HEK293 cells, hyperkalemic conditions (18.6mM potassium concentrations), BPC 157 directly affects potassium conductance, counteracting the effect on membrane potential and depolarizations caused by hyperkalemic conditions.
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Affiliation(s)
- Ivan Barisic
- Department of Pharmacology, University of Zagreb, Medical School, Salata 11, 10000 Zagreb, Croatia
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Cesarec V, Becejac T, Misic M, Djakovic Z, Olujic D, Drmic D, Brcic L, Rokotov DS, Seiwerth S, Sikiric P. Pentadecapeptide BPC 157 and the esophagocutaneous fistula healing therapy. Eur J Pharmacol 2012; 701:203-12. [PMID: 23220707 DOI: 10.1016/j.ejphar.2012.11.055] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2012] [Revised: 11/26/2012] [Accepted: 11/28/2012] [Indexed: 02/07/2023]
Abstract
Esophagocutaneous fistulas are a failure of the NO-system, due to NO-synthase blockage by the NOS-blocker L-NAME consequently counteracted by l-arginine and gastric pentadecapeptide BPC 157 (l-arginine <BPC 157), precipitating a therapeutic benefit. Previously, there was an established BPC 157-NO-system interaction. BPC 157 GEPPPGKPADDAGLV, MW 1419 (LD1 not achieved), is a safe and stable anti-ulcer peptide, successful in inflammatory bowel disease trials, counteracting esophagitis, sphincter failure, gastrointestinal and skin ulcers, gastrocutaneous or colocutaneous fistulas. We treated rats with established cervical esophagocutaneous fistulas throughout four days (both open skin and esophageal defects, with significant leakage) with BPC 157 (parenterally and perorally) and L-NAME (blocking NO genesis) and l-arginine (NO-substrate) alone or in combination. RT-PCR investigated eNOS, iNOS, COX-2 mRNA levels in the fistulas. We evidenced a closely inter-related process of unhealed skin, esophageal defects, unhealed fistulas (up regulated eNOS, iNOS and COX2 mRNA levels), usually lethal, particularly NO-system related and therapy dependent. Generally, the course of fistula healing was accelerated either to a greater extent (with BPC 157 (in particular, less eNOS gene expression) completely counteracting L-NAME effects, in L-NAME+BPC 157 and L-NAME+l-arginine+BPC 157 groups), or to a lesser extent (with l-arginine). Conversely, the process was aggravated, rapidly and prominently (with L-NAME). In particular, BPC 157 was effective either given per-orally/intraperitoneally, in μg- and ng-regimens. Shortly, defects started to heal, with less fistula leakage and no mortality at day 4. Failure of pyloric and lower esophageal sphincter pressure was restored, with practically no esophagitis.
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Affiliation(s)
- Vedran Cesarec
- Department of Pharmacology, University of Zagreb, Zagreb, Croatia
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