|
1
|
Sikiric P, Sever M, Krezic I, Vranes H, Kalogjera L, Smoday IM, Vukovic V, Oroz K, Coric L, Skoro M, Kavelj I, Zubcic S, Sikiric S, Beketic Oreskovic L, Oreskovic I, Blagaic V, Brcic K, Strbe S, Staresinic M, Boban Blagaic A, Skrtic A, Seiwerth S. New studies with stable gastric pentadecapeptide protecting gastrointestinal tract. significance of counteraction of vascular and multiorgan failure of occlusion/occlusion-like syndrome in cytoprotection/organoprotection. Inflammopharmacology 2024; 32:3119-3161. [PMID: 38980576 DOI: 10.1007/s10787-024-01499-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2024] [Accepted: 05/28/2024] [Indexed: 07/10/2024]
Abstract
Since the early 1990s, when Robert's and Szabo's cytoprotection concept had already been more than one decade old, but still not implemented in therapy, we suggest the stable gastric pentadecapeptide BPC 157 as the most relevant mediator of the cytoprotection concept. Consequently, it can translate stomach and gastrointestinal mucosal maintenance, epithelium, and endothelium cell protection to the therapy of other tissue healing (organoprotection), easily applicable, as native and stable in human gastric juice for more than 24 h. These overwhelm current clinical evidence (i.e., ulcerative colitis, phase II, no side effects, and no lethal dose (LD1) in toxicology studies), as BPC 157 therapy effectively combined various tissue healing and lesions counteraction. BPC 157 cytoprotection relevance and vascular recovery, activation of collateral pathways, membrane stabilizer, eye therapy, wound healing capability, brain-gut and gut-brain functioning, tumor cachexia counteraction, muscle, tendon, ligament, and bone disturbances counteraction, and the heart disturbances, myocardial infarction, heart failure, pulmonary hypertension, arrhythmias, and thrombosis counteraction appeared in the recent reviews. Here, as concept resolution, we review the counteraction of advanced Virchow triad circumstances by activation of the collateral rescuing pathways, depending on injury, activated azygos vein direct blood flow delivery, to counteract occlusion/occlusion-like syndromes starting with the context of alcohol-stomach lesions. Counteraction of major vessel failure (congested inferior caval vein and superior mesenteric vein, collapsed azygos vein, collapsed abdominal aorta) includes counteraction of the brain (intracerebral and intraventricular hemorrhage), heart (congestion, severe arrhythmias), lung (hemorrhage), and congestion and lesions in the liver, kidney, and gastrointestinal tract, intracranial (superior sagittal sinus), portal and caval hypertension, aortal hypotension, and thrombosis, peripherally and centrally.
Collapse
Affiliation(s)
- Predrag Sikiric
- Department of Pharmacology, School of Medicine, University of Zagreb, Zagreb, Croatia.
| | - Marko Sever
- Department of Pharmacology, School of Medicine, University of Zagreb, Zagreb, Croatia
- Department of Surgery, School of Medicine, University of Zagreb, Zagreb, Croatia
| | - Ivan Krezic
- Department of Pharmacology, School of Medicine, University of Zagreb, Zagreb, Croatia
| | - Hrvoje Vranes
- Department of Pharmacology, School of Medicine, University of Zagreb, Zagreb, Croatia
| | - Luka Kalogjera
- Department of Pharmacology, School of Medicine, University of Zagreb, Zagreb, Croatia
| | - Ivan Maria Smoday
- Department of Pharmacology, School of Medicine, University of Zagreb, Zagreb, Croatia
| | - Vlasta Vukovic
- Department of Pharmacology, School of Medicine, University of Zagreb, Zagreb, Croatia
| | - Katarina Oroz
- Department of Pharmacology, School of Medicine, University of Zagreb, Zagreb, Croatia
| | - Luka Coric
- Department of Pharmacology, School of Medicine, University of Zagreb, Zagreb, Croatia
| | - Marija Skoro
- Department of Pharmacology, School of Medicine, University of Zagreb, Zagreb, Croatia
- Department of Diagnostic and Interventional Radiology, Sestre Milosrdnice University Hospital Center, Zagreb, Croatia
| | - Ivana Kavelj
- Department of Pharmacology, School of Medicine, University of Zagreb, Zagreb, Croatia
- Department of Diagnostic and Interventional Radiology, Sestre Milosrdnice University Hospital Center, Zagreb, Croatia
| | - Slavica Zubcic
- Department of Pharmacology, School of Medicine, University of Zagreb, Zagreb, Croatia
| | - Suncana Sikiric
- Department of Pathology, School of Medicine, University of Zagreb, 10000, Zagreb, Croatia
| | | | - Ivana Oreskovic
- Department of Pharmacology, School of Medicine, University of Zagreb, Zagreb, Croatia
| | - Vladimir Blagaic
- Department of Pharmacology, School of Medicine, University of Zagreb, Zagreb, Croatia
| | - Klara Brcic
- Department of Pharmacology, School of Medicine, University of Zagreb, Zagreb, Croatia
| | - Sanja Strbe
- Department of Pharmacology, School of Medicine, University of Zagreb, Zagreb, Croatia
| | - Mario Staresinic
- Department of Pharmacology, School of Medicine, University of Zagreb, Zagreb, Croatia
- Department of Surgery, School of Medicine, University of Zagreb, Zagreb, Croatia
| | - Alenka Boban Blagaic
- Department of Pharmacology, School of Medicine, University of Zagreb, Zagreb, Croatia
| | - Anita Skrtic
- Department of Pathology, School of Medicine, University of Zagreb, 10000, Zagreb, Croatia
| | - Sven Seiwerth
- Department of Pathology, School of Medicine, University of Zagreb, 10000, Zagreb, Croatia
| |
Collapse
|
|
2
|
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.
Collapse
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
| |
Collapse
|
|
3
|
Sikiric P, Gojkovic S, Krezic I, Smoday IM, Kalogjera L, Zizek H, Oroz K, Vranes H, Vukovic V, Labidi M, Strbe S, Baketic Oreskovic L, Sever M, Tepes M, Knezevic M, Barisic I, Blagaic V, Vlainic J, Dobric I, Staresinic M, Skrtic A, Jurjevic I, Boban Blagaic A, Seiwerth S. Stable Gastric Pentadecapeptide BPC 157 May Recover Brain-Gut Axis and Gut-Brain Axis Function. Pharmaceuticals (Basel) 2023; 16:ph16050676. [PMID: 37242459 DOI: 10.3390/ph16050676] [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: 03/09/2023] [Revised: 04/12/2023] [Accepted: 04/25/2023] [Indexed: 05/28/2023] Open
Abstract
Conceptually, a wide beneficial effect, both peripherally and centrally, might have been essential for the harmony of brain-gut and gut-brain axes' function. Seen from the original viewpoint of the gut peptides' significance and brain relation, the favorable stable gastric pentadecapeptide BPC 157 evidence in the brain-gut and gut-brain axes' function might have been presented as a particular interconnected network. These were the behavioral findings (interaction with main systems, anxiolytic, anticonvulsive, antidepressant effect, counteracted catalepsy, and positive and negative schizophrenia symptoms models). Muscle healing and function recovery appeared as the therapeutic effects of BPC 157 on the various muscle disabilities of a multitude of causes, both peripheral and central. Heart failure was counteracted (including arrhythmias and thrombosis), and smooth muscle function recovered. These existed as a multimodal muscle axis impact on muscle function and healing as a function of the brain-gut axis and gut-brain axis as whole. Finally, encephalopathies, acting simultaneously in both the periphery and central nervous system, BPC 157 counteracted stomach and liver lesions and various encephalopathies in NSAIDs and insulin rats. BPC 157 therapy by rapidly activated collateral pathways counteracted the vascular and multiorgan failure concomitant to major vessel occlusion and, similar to noxious procedures, reversed initiated multicausal noxious circuit of the occlusion/occlusion-like syndrome. Severe intracranial (superior sagittal sinus) hypertension, portal and caval hypertensions, and aortal hypotension were attenuated/eliminated. Counteracted were the severe lesions in the brain, lungs, liver, kidney, and gastrointestinal tract. In particular, progressing thrombosis, both peripherally and centrally, and heart arrhythmias and infarction that would consistently occur were fully counteracted and/or almost annihilated. To conclude, we suggest further BPC 157 therapy applications.
Collapse
Affiliation(s)
- Predrag Sikiric
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia
| | - Slaven Gojkovic
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia
| | - Ivan Krezic
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia
| | - Ivan Maria Smoday
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia
| | - Luka Kalogjera
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia
| | - Helena Zizek
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia
| | - Katarina Oroz
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia
| | - Hrvoje Vranes
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia
| | - Vlasta Vukovic
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia
| | - May Labidi
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia
| | - Sanja Strbe
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia
| | | | - Marko Sever
- Department of Surgery, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia
| | - Marijan Tepes
- Department of Clinical Medicine, Faculty of Dental Medicine and Health, University of Osijek, 31000 Osijek, Croatia
| | - Mario Knezevic
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia
| | - Ivan Barisic
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia
| | - Vladimir Blagaic
- Department of Obstetrics and Gynecology, Clinical Hospital Sveti Duh, 10000 Zagreb, Croatia
| | - Josipa Vlainic
- Laboratory for Advanced Genomics, Division of Molecular Medicine, lnstitute Ruder Boskovic, 10000 Zagreb, Croatia
| | - Ivan Dobric
- Department of Surgery, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia
| | - Mario Staresinic
- Department of Surgery, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia
| | - Anita Skrtic
- Department of Pathology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia
| | - Ivana Jurjevic
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia
| | - Alenka Boban Blagaic
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia
| | - Sven Seiwerth
- Department of Pathology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia
| |
Collapse
|
|
4
|
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).
Collapse
|
|
5
|
Stable Gastric Pentadecapeptide BPC 157 as Useful Cytoprotective Peptide Therapy in the Heart Disturbances, Myocardial Infarction, Heart Failure, Pulmonary Hypertension, Arrhythmias, and Thrombosis Presentation. Biomedicines 2022; 10:biomedicines10112696. [PMID: 36359218 PMCID: PMC9687817 DOI: 10.3390/biomedicines10112696] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2022] [Revised: 10/08/2022] [Accepted: 10/15/2022] [Indexed: 11/30/2022] Open
Abstract
In heart disturbances, stable gastric pentadecapeptide BPC 157 especial therapy effects combine the therapy of myocardial infarction, heart failure, pulmonary hypertension arrhythmias, and thrombosis prevention and reversal. The shared therapy effect occurred as part of its even larger cytoprotection (cardioprotection) therapy effect (direct epithelial cell protection; direct endothelium cell protection) that BPC 157 exerts as a novel cytoprotection mediator, which is native and stable in human gastric juice, as well as easily applicable. Accordingly, there is interaction with many molecular pathways, combining maintained endothelium function and maintained thrombocytes function, which counteracted thrombocytopenia in rats that underwent major vessel occlusion and deep vein thrombosis and counteracted thrombosis in all vascular studies; the coagulation pathways were not affected. These appeared as having modulatory effects on NO-system (NO-release, NOS-inhibition, NO-over-stimulation all affected), controlling vasomotor tone and the activation of the Src-Caveolin-1-eNOS pathway and modulatory effects on the prostaglandins system (BPC 157 counteracted NSAIDs toxicity, counteracted bleeding, thrombocytopenia, and in particular, leaky gut syndrome). As an essential novelty noted in the vascular studies, there was the activation of the collateral pathways. This might be the upgrading of the minor vessel to take over the function of the disabled major vessel, competing with and counteracting the Virchow triad circumstances devastatingly present, making possible the recruitment of collateral blood vessels, compensating vessel occlusion and reestablishing the blood flow or bypassing the occluded or ruptured vessel. As a part of the counteraction of the severe vessel and multiorgan failure syndrome, counteracted were the brain, lung, liver, kidney, gastrointestinal lesions, and in particular, the counteraction of the heart arrhythmias and infarction.
Collapse
|
|
6
|
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.
Collapse
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
| |
Collapse
|
|
7
|
Feng XY, Xue H, Guo ZH, Yan JT, Liu S, Zhu JX. Dopamine and Gastrointestinal Mucosa Function. DOPAMINE IN THE GUT 2021:87-131. [DOI: 10.1007/978-981-33-6586-5_4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/02/2025]
|
|
8
|
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.
Collapse
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.
| |
Collapse
|
|
9
|
Kolovrat M, Gojkovic S, Krezic I, Malekinusic D, Vrdoljak B, Kasnik Kovac K, Kralj T, Drmic D, Barisic I, Horvat Pavlov K, Petrovic A, Duzel A, Knezevic M, Mirkovic I, Kokot A, Boban Blagaic A, Seiwerth S, Sikiric P. Pentadecapeptide BPC 157 resolves Pringle maneuver in rats, both ischemia and reperfusion. World J Hepatol 2020; 12:184-206. [PMID: 32547687 PMCID: PMC7280862 DOI: 10.4254/wjh.v12.i5.184] [Citation(s) in RCA: 35] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/23/2019] [Revised: 03/25/2020] [Accepted: 03/30/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND The Pringle maneuver [portal triad obstruction(PTO)] provides huge disturbances during ischemia and even more thereafter in reperfusion. Contrarily, a possible solution may be stable gastric pentadecapeptide BPC 157, with already documented beneficial effects in ischemia/reperfusion conditions. Recently, BPC 157, as a cytoprotective agent, successfully resolved vessel occlusions in rats (ischemic colitis; deep vein thrombosis, superior anterior pancreaticoduodenal vein; bile duct cirrhosis) through rapid collateral vessel recruitment to circumvent vessel occlusion. Thereby, medication BPC 157 regimens were administered as a single challenge before and during ischemia or, alternatively, at various time points during reperfusion.
AIM To introduce BPC 157 therapy against pringle maneuver-damage.
METHODS In deeply anesthetised rats, the portal triad was clamped up for 30 min. Rats then underwent reperfusion for either 15 min or 24 h. Medication [(10 µg, 10 ng/kg) regimens, administered as a single challenge] picked (a) ischemia, PTO period [at 5 min before (ip) or at 5 or 30 min of ligation time (as a bath to PTO)] or (b) reperfusion, post-PTO period [at 1 or 15 min (bath during surgery) or 24 h (ip) reperfusion-time]. We provided gross, microscopy, malondialdehyde, serum enzymes, electrocardiogram, portal, caval, and aortal pressure, thrombosis and venography assessments.
RESULTS BPC 157 counteracts electrocardiogram disturbances (increased P wave amplitude, S1Q3T3 QRS pattern and tachycardia). Rapidly presented vascular pathway (portal vein-superior mesenteric vein-inferior mesenteric vein-rectal veins-left ileal vein-inferior caval vein) as the adequate shunting immediately affected disturbed haemodynamics. Portal hypertension and severe aortal hypotension during PTO, as well as portal and caval hypertension and mild aortal hypotension in reperfusion and refractory ascites formation were markedly attenuated (during PTO) or completely abrogated (reperfusion); thrombosis in portal vein tributaries and inferior caval vein or hepatic artery was counteracted during portal triad obstruction PTO. Also, counteraction included the whole vicious injurious circle [i.e., lung pathology (severe capillary congestion), liver (dilated central veins and terminal portal venules), intestine (substantial capillary congestion, submucosal oedema, loss of villous architecture), splenomegaly, right heart (picked P wave values)] regularly perpetuated in ischemia and progressed by reperfusion in Pringle rats.
CONCLUSION BPC 157 resolves pringle maneuver-damage in rats, both for ischemia and reperfusion.
Collapse
Affiliation(s)
- Marijan Kolovrat
- Departments of Pharmacology and Pathology, School of Medicine, University of Zagreb, Zagreb 10000, Croatia
| | - Slaven Gojkovic
- Departments of Pharmacology and Pathology, School of Medicine, University of Zagreb, Zagreb 10000, Croatia
| | - Ivan Krezic
- Departments of Pharmacology and Pathology, School of Medicine, University of Zagreb, Zagreb 10000, Croatia
| | - Dominik Malekinusic
- Departments of Pharmacology and Pathology, School of Medicine, University of Zagreb, Zagreb 10000, Croatia
| | - Borna Vrdoljak
- Departments of Pharmacology and Pathology, School of Medicine, University of Zagreb, Zagreb 10000, Croatia
| | - Katarina Kasnik Kovac
- Departments of Pharmacology and Pathology, School of Medicine, University of Zagreb, Zagreb 10000, Croatia
| | - Tamara Kralj
- Departments of Pharmacology and Pathology, School of Medicine, University of Zagreb, Zagreb 10000, Croatia
| | - Domagoj Drmic
- Departments of Pharmacology and Pathology, School of Medicine, University of Zagreb, Zagreb 10000, Croatia
| | - Ivan Barisic
- Departments of Pharmacology and Pathology, School of Medicine, University of Zagreb, Zagreb 10000, Croatia
| | - Katarina Horvat Pavlov
- Departments of Pharmacology and Pathology, School of Medicine, University of Zagreb, Zagreb 10000, Croatia
| | - Andreja Petrovic
- Departments of Pharmacology and Pathology, School of Medicine, University of Zagreb, Zagreb 10000, Croatia
| | - Antonija Duzel
- Departments of Pharmacology and Pathology, School of Medicine, University of Zagreb, Zagreb 10000, Croatia
| | - Mario Knezevic
- Departments of Pharmacology and Pathology, School of Medicine, University of Zagreb, Zagreb 10000, Croatia
| | - Ivan Mirkovic
- Departments of Pharmacology and Pathology, School of Medicine, University of Zagreb, Zagreb 10000, Croatia
| | - Antonio Kokot
- Departments of Pharmacology and Pathology, School of Medicine, University of Zagreb, Zagreb 10000, Croatia
| | - Alenka Boban Blagaic
- Departments of Pharmacology and Pathology, School of Medicine, University of Zagreb, Zagreb 10000, Croatia
| | - Sven Seiwerth
- Departments of Pharmacology and Pathology, School of Medicine, University of Zagreb, Zagreb 10000, Croatia
| | - Predrag Sikiric
- Departments of Pharmacology and Pathology, School of Medicine, University of Zagreb, Zagreb 10000, Croatia
| |
Collapse
|
|
10
|
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.
Collapse
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.
| |
Collapse
|
|
11
|
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).
Collapse
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
| |
Collapse
|
|
12
|
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.
Collapse
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
| |
Collapse
|
|
13
|
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.
Collapse
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.
| |
Collapse
|
|
14
|
Strinic D, Belosic Halle Z, Luetic K, Nedic A, Petrovic I, Sucic M, Zivanovic Posilovic G, Balenovic D, Strbe S, Udovicic M, Drmic D, Stupnisek M, Lovric Bencic M, Seiwerth S, Sikiric P. BPC 157 counteracts QTc prolongation induced by haloperidol, fluphenazine, clozapine, olanzapine, quetiapine, sulpiride, and metoclopramide in rats. Life Sci 2017; 186:66-79. [PMID: 28797793 DOI: 10.1016/j.lfs.2017.08.006] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2017] [Revised: 07/27/2017] [Accepted: 08/06/2017] [Indexed: 12/27/2022]
Abstract
AIM Commonly, neuroleptics and prokinetics induce a prolonged QTc interval. In this study, stable gastric pentadecapeptide BPC 157 counteracts the prolongation of the QTc interval in Wistar rats that underwent daily administration of dopamine neuroleptics or prokinetics. Previously, in rats and mice, BPC 157 counteracted neuroleptic-induced catalepsy and gastric ulcers. MAIN METHODS To counteract neuroleptic- or prokinetic-induced prolongation of the QTc interval, rats were given a BPC 157 regimen once daily over seven days (10μg, 10ng/kg ip) immediately after each administrations of haloperidol (0.625, 6.25, 12.5, and 25.0mg/kg ip), fluphenazine (0.5, 5.0mg/kg ip), clozapine (1.0, 10.0mg/kg ip), quetiapine (1.0, 10.0mg/kg ip), sulpiride (1.6, 16.0mg/kg ip), metoclopramide (2.5, 25.0mg/kg ip) or (1.0, 10.0mg/kg ip). Controls simultaneously received saline (5ml/kg ip). To assess the ECG presentation before and after neuroleptic/prokinetic medication, the assessment was at 1, 2, 3, 4, 5, 10, 15, 20 and 30min (first administration) as well as at 30min, 60min and 24h (first administration and subsequent administrations) and the ECG recording started prior to drug administration. KEY FINDINGS Since very early, a prolonged QTc interval has been continually noted with haloperidol, fluphenazine, clozapine, olanzapine, quetiapine, sulpiride, and metoclopramide in rats as a central common effect not seen with domperidone. Consistent counteraction appears with the stable gastric pentadecapeptide BPC 157. Thus, BPC 157 rapidly and permanently counteracts the QTc prolongation induced by neuroleptics and prokinetics. SIGNIFICANCE Pentadecapeptide BPC 157 is suited for counteracting a prolonged QT interval.
Collapse
Affiliation(s)
- Dean Strinic
- Departments of Pharmacology & Pathology, Medical Faculty University of Zagreb, Zagreb, Croatia; Faculty of Medicine, J.J. Strossmayer University of Osijek, Osijek, Croatia
| | - Zeljka Belosic Halle
- Departments of Pharmacology & Pathology, Medical Faculty University of Zagreb, Zagreb, Croatia; Faculty of Medicine, J.J. Strossmayer University of Osijek, Osijek, Croatia
| | - Kresimir Luetic
- Departments of Pharmacology & Pathology, Medical Faculty University of Zagreb, Zagreb, Croatia; Faculty of Medicine, J.J. Strossmayer University of Osijek, Osijek, Croatia
| | - Ana Nedic
- Departments of Pharmacology & Pathology, Medical Faculty University of Zagreb, Zagreb, Croatia; Faculty of Medicine, J.J. Strossmayer University of Osijek, Osijek, Croatia
| | - Igor Petrovic
- Departments of Pharmacology & Pathology, Medical Faculty University of Zagreb, Zagreb, Croatia; Faculty of Medicine, J.J. Strossmayer University of Osijek, Osijek, Croatia
| | - Mario Sucic
- Departments of Pharmacology & Pathology, Medical Faculty University of Zagreb, Zagreb, Croatia; Faculty of Medicine, J.J. Strossmayer University of Osijek, Osijek, Croatia
| | - Gordana Zivanovic Posilovic
- Departments of Pharmacology & Pathology, Medical Faculty University of Zagreb, Zagreb, Croatia; Faculty of Medicine, J.J. Strossmayer University of Osijek, Osijek, Croatia
| | - Dijana Balenovic
- Departments of Pharmacology & Pathology, Medical Faculty University of Zagreb, Zagreb, Croatia; Faculty of Medicine, J.J. Strossmayer University of Osijek, Osijek, Croatia
| | - Sanja Strbe
- Departments of Pharmacology & Pathology, Medical Faculty University of Zagreb, Zagreb, Croatia; Faculty of Medicine, J.J. Strossmayer University of Osijek, Osijek, Croatia
| | - Mario Udovicic
- Departments of Pharmacology & Pathology, Medical Faculty University of Zagreb, Zagreb, Croatia; Faculty of Medicine, J.J. Strossmayer University of Osijek, Osijek, Croatia
| | - Domagoj Drmic
- Departments of Pharmacology & Pathology, Medical Faculty University of Zagreb, Zagreb, Croatia; Faculty of Medicine, J.J. Strossmayer University of Osijek, Osijek, Croatia
| | - Mirjana Stupnisek
- Departments of Pharmacology & Pathology, Medical Faculty University of Zagreb, Zagreb, Croatia; Faculty of Medicine, J.J. Strossmayer University of Osijek, Osijek, Croatia
| | - Martina Lovric Bencic
- Departments of Pharmacology & Pathology, Medical Faculty University of Zagreb, Zagreb, Croatia; Faculty of Medicine, J.J. Strossmayer University of Osijek, Osijek, Croatia
| | - Sven Seiwerth
- Departments of Pharmacology & Pathology, Medical Faculty University of Zagreb, Zagreb, Croatia; Faculty of Medicine, J.J. Strossmayer University of Osijek, Osijek, Croatia
| | - Predrag Sikiric
- Departments of Pharmacology & Pathology, Medical Faculty University of Zagreb, Zagreb, Croatia; Faculty of Medicine, J.J. Strossmayer University of Osijek, Osijek, Croatia.
| |
Collapse
|
|
15
|
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.
Collapse
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.
| |
Collapse
|
|
16
|
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.
Collapse
Affiliation(s)
- Predrag Sikiric
- Medical Faculty, University of Zagreb, Šalata 3, 10000 Zagreb, Croatia
| | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
17
|
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).
Collapse
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.
| |
Collapse
|
|
18
|
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.
Collapse
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
| |
Collapse
|
|
19
|
Tressler J, Schwartz C, Wellman P, Hughes S, Smotherman M. Regulation of bat echolocation pulse acoustics by striatal dopamine. ACTA ACUST UNITED AC 2012; 214:3238-47. [PMID: 21900471 DOI: 10.1242/jeb.058149] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
The ability to control the bandwidth, amplitude and duration of echolocation pulses is a crucial aspect of echolocation performance but few details are known about the neural mechanisms underlying the control of these voice parameters in any mammal. The basal ganglia (BG) are a suite of forebrain nuclei centrally involved in sensory-motor control and are characterized by their dependence on dopamine. We hypothesized that pharmacological manipulation of brain dopamine levels could reveal how BG circuits might influence the acoustic structure of bat echolocation pulses. A single intraperitoneal injection of a low dose (5 mg kg(-1)) of the neurotoxin 1-methyl-4-phenylpyridine (MPTP), which selectively targets dopamine-producing cells of the substantia nigra, produced a rapid degradation in pulse acoustic structure and eliminated the bat's ability to make compensatory changes in pulse amplitude in response to background noise, i.e. the Lombard response. However, high-performance liquid chromatography (HPLC) measurements of striatal dopamine concentrations revealed that the main effect of MPTP was a fourfold increase rather than the predicted decrease in striatal dopamine levels. After first using autoradiographic methods to confirm the presence and location of D(1)- and D(2)-type dopamine receptors in the bat striatum, systemic injections of receptor subtype-specific agonists showed that MPTP's effects on pulse acoustics were mimicked by a D(2)-type dopamine receptor agonist (Quinpirole) but not by a D(1)-type dopamine receptor agonist (SKF82958). The results suggest that BG circuits have the capacity to influence echolocation pulse acoustics, particularly via D(2)-type dopamine receptor-mediated pathways, and may therefore represent an important mechanism for vocal control in bats.
Collapse
Affiliation(s)
- Jedediah Tressler
- Department of Biology, Texas A&M University, 3258 TAMU, College Station, TX 77843-3258, USA
| | | | | | | | | |
Collapse
|
|
20
|
Cellular localization of dopamine receptors in the gastric mucosa of rats. Biochem Biophys Res Commun 2011; 417:197-203. [PMID: 22155235 DOI: 10.1016/j.bbrc.2011.11.084] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2011] [Accepted: 11/16/2011] [Indexed: 11/23/2022]
Abstract
Dopamine (DA) plays a critical role in the protection of gastric mucosa and is mediated through corresponding receptors. However, the details of the expression of DA receptors (D1-D5) in the gastric mucosa are lacking. The present study investigated the expression and cellular localization of DA receptors in rat gastric mucosa by means of real-time PCR and immunofluorescent techniques. The results indicated that the mRNA expressions of all five subtypes of DA receptors were found in the gastric mucosa, among which the D2 level was the highest. The immunopositive cells of D1-D3 and D5 were primarily localized to the basilar gland of the epithelial layer in gastric corpus, but D4 immunoreactivity (IR) was only observed in the enteric nerve plexus. The D1, D2, and D5 IR were found in pepsin C-IR cells except D3. No IR of any DA receptor was detected in the H(+)/K(+)-ATPase- or mucin 6-IR cells. In conclusion, for the first time, this study demonstrates the predominant distribution of DA receptors in the chief cells, not the parietal and mucous neck cells, in rat gastric mucosa, thus suggesting that DA may not directly regulate the function of parietal cells or mucous neck cells, but it may modulate the function of chief cells through the D1, D2, and D5 receptors.
Collapse
|
|
21
|
Ilic S, Drmic D, Zarkovic K, Kolenc D, Brcic L, Radic B, Djuzel V, Blagaic AB, Romic Z, Dzidic S, Kalogjera L, Seiwerth S, Sikiric P. Ibuprofen hepatic encephalopathy, hepatomegaly, gastric lesion and gastric pentadecapeptide BPC 157 in rats. Eur J Pharmacol 2011; 667:322-9. [PMID: 21645505 DOI: 10.1016/j.ejphar.2011.05.038] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2010] [Revised: 05/12/2011] [Accepted: 05/22/2011] [Indexed: 02/07/2023]
Abstract
Chronic ibuprofen (0.4 g/kg intraperitoneally, once daily for 4 weeks) evidenced a series of pathologies, not previously reported in ibuprofen-dosed rats, namely hepatic encephalopathy, gastric lesions, hepatomegaly, increased AST and ALT serum values with prolonged sedation/unconsciousness, and weight loss. In particular, ibuprofen toxicity was brain edema, particularly in the cerebellum, with the white matter being more affected than in gray matter. In addition, damaged and red neurons, in the absence of anti-inflammatory reaction was observed, particularly in the cerebral cortex and cerebellar nuclei, but was also present although to a lesser extent in the hippocampus, dentate nucleus and Purkinje cells. An anti-ulcer peptide shown to have no toxicity, the stable gastric pentadecapeptide BPC 157 (GEPPPGKPADDAGLV, MW 1419, 10 μg, 10 ng/kg) inhibited the pathology seen with ibuprofen (i) when given intraperitoneally, immediately after ibuprofen daily or (ii) when given in drinking water (0.16 μg, 0.16 ng/ml). Counteracted were all adverse effects, such as hepatic encephalopathy, the gastric lesions, hepatomegaly, increased liver serum values. In addition, BPC 157 treated rats showed no behavioral disturbances and maintained normal weight gain. Thus, apart from efficacy in inflammatory bowel disease and various wound treatments, BPC 157 was also effective when given after ibuprofen.
Collapse
Affiliation(s)
- Spomenko Ilic
- Department of Pharmacology and Pathology Medical Faculty University of Zagreb, Zagreb, Croatia
| | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
22
|
Ilic S, Drmic D, Franjic S, Kolenc D, Coric M, Brcic L, Klicek R, Radic B, Sever M, Djuzel V, Filipovic M, Djakovic Z, Stambolija V, Blagaic AB, Zoricic I, Gjurasin M, Stupnisek M, Romic Z, Zarkovic K, Dzidic S, Seiwerth S, Sikiric P. Pentadecapeptide BPC 157 and its effects on a NSAID toxicity model: diclofenac-induced gastrointestinal, liver, and encephalopathy lesions. Life Sci 2011; 88:535-42. [PMID: 21295044 DOI: 10.1016/j.lfs.2011.01.015] [Citation(s) in RCA: 51] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2010] [Revised: 12/23/2010] [Accepted: 01/05/2011] [Indexed: 02/07/2023]
Abstract
AIMS We attempted to fully antagonize the extensive toxicity caused by NSAIDs (using diclofenac as a prototype). MAIN METHODS Herein, we used the stable gastric pentadecapeptide BPC 157 (GEPPPGKPADDAGLV, MW 1419), an anti-ulcer peptide shown to be efficient in inflammatory bowel disease clinical trials (PL 14736) and various wound treatments with no toxicity reported. This peptide was given to antagonize combined gastrointestinal, liver, and brain toxicity induced by diclofenac (12.5mg/kg intraperitoneally, once daily for 3 days) in rats. KEY FINDINGS Already considered a drug that can reverse the toxic side effects of NSAIDs, BPC 157 (10 μg/kg, 10 ng/kg) was strongly effective throughout the entire experiment when given (i) intraperitoneally immediately after diclofenac or (ii) per-orally in drinking water (0.16 μg/mL, 0.16 ng/mL). Without BPC 157 treatment, at 3h following the last diclofenac challenge, we encountered a complex deleterious circuit of diclofenac toxicity characterized by severe gastric, intestinal and liver lesions, increased bilirubin, aspartate transaminase (AST), alanine transaminase (ALT) serum values, increased liver weight, prolonged sedation/unconsciousness (after any diclofenac challenge) and finally hepatic encephalopathy (brain edema particularly located in the cerebral cortex and cerebellum, more in white than in gray matter, damaged red neurons, particularly in the cerebral cortex and cerebellar nuclei, Purkinje cells and less commonly in the hippocampal neurons). SIGNIFICANCE The very extensive antagonization of diclofenac toxicity achieved with BPC 157 (μg-/ng-regimen, intraperitoneally, per-orally) may encourage its further use as a therapy to counteract diclofenac- and other NSAID-induced toxicity.
Collapse
Affiliation(s)
- Spomenko Ilic
- Department of Pharmacology and Pathology Medical Faculty, University of Zagreb, Zagreb, Croatia
| | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
23
|
Borah A, Mohanakumar KP. l-DOPA-induced 6-hydroxydopamine production in the striata of rodents is sensitive to the degree of denervation. Neurochem Int 2010; 56:357-62. [DOI: 10.1016/j.neuint.2009.11.008] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2009] [Revised: 11/10/2009] [Accepted: 11/11/2009] [Indexed: 11/17/2022]
|
|
24
|
Tudor M, Jandric I, Marovic A, Gjurasin M, Perovic D, Radic B, Blagaic AB, Kolenc D, Brcic L, Zarkovic K, Seiwerth S, Sikiric P. Traumatic brain injury in mice and pentadecapeptide BPC 157 effect. ACTA ACUST UNITED AC 2009; 160:26-32. [PMID: 19931318 DOI: 10.1016/j.regpep.2009.11.012] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2009] [Revised: 11/11/2009] [Accepted: 11/12/2009] [Indexed: 01/18/2023]
Abstract
Gastric pentadecapeptide BPC 157 (GEPPPGKPADDAGLV, an anti-ulcer peptide, efficient in inflammatory bowel disease trials (PL 14736), no toxicity reported, improved muscle crush injury. After an induced traumatic brain injury (TBI) in mice by a falling weight, BPC 157 regimens (10.0microg, 10.0ng/kgi.p.) demonstrated a marked attenuation of damage with an improved early outcome and a minimal postponed mortality throughout a 24h post-injury period. Ultimately, the traumatic lesions (subarachnoidal and intraventricular haemorrhage, brain laceration, haemorrhagic laceration) were less intense and consecutive brain edema had considerably improved. Given prophylactically (30 min before TBI) the improved conscious/unconscious/death ratio in TBI-mice was after force impulses of 0.068 Ns, 0.093 Ns, 0.113 Ns, 0.130 Ns, 0.145 Ns, and 0.159 Ns. Counteraction (with a reduction of unconsciousness, lower mortality) with both microg- and ng-regimens included the force impulses of 0.068-0.145 Ns. A higher regimen presented effectiveness also against the maximal force impulse (0.159 Ns). Furthermore, BPC 157 application immediately prior to injury was beneficial in mice subjected to force impulses of 0.093 Ns-TBI. For a more severe force impulse (0.130 Ns, 0.145 Ns, or 0159 Ns), the time-relation to improve the conscious/unconscious/death ratio was: 5 min (0.130 Ns-TBI), 20 min (0.145 Ns-TBI) or 30 min (0.159 Ns-TBI).
Collapse
Affiliation(s)
- Mario Tudor
- Department of Pharmacology, Medical Faculty University of Zagreb, 10000 Zagreb, Croatia
| | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
25
|
Gjurasin M, Miklic P, Zupancic B, Perovic D, Zarkovic K, Brcic L, Kolenc D, Radic B, Seiwerth S, Sikiric P. Peptide therapy with pentadecapeptide BPC 157 in traumatic nerve injury. ACTA ACUST UNITED AC 2009; 160:33-41. [PMID: 19903499 DOI: 10.1016/j.regpep.2009.11.005] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2009] [Revised: 09/23/2009] [Accepted: 11/01/2009] [Indexed: 12/22/2022]
Abstract
We focused on the healing of rat transected sciatic nerve and improvement made by stable gastric pentadecapeptide BPC 157 (10 microg, 10ng/kg) applied shortly after injury (i) intraperitoneally/intragastrically/locally, at the site of anastomosis, or after (ii) non-anastomozed nerve tubing (7 mm nerve segment resected) directly into the tube. Improvement was shown clinically (autotomy), microscopically/morphometrically and functionally (EMG, one or two months post-injury, walking recovery (sciatic functional index (SFI)) at weekly intervals). BPC 157-rats exhibited faster axonal regeneration: histomorphometrically (improved presentation of neural fascicles, homogeneous regeneration pattern, increased density and size of regenerative fibers, existence of epineural and perineural regeneration, uniform target orientation of regenerative fibers, and higher proportion of neural vs. connective tissue, all fascicles in each nerve showed increased diameter of myelinated fibers, thickness of myelin sheet, number of myelinated fibers per area and myelinated fibers as a percentage of the nerve transected area and the increased blood vessels presentation), electrophysiologically (increased motor action potentials), functionally (improved SFI), the autotomy absent. Thus, BPC 157 markedly improved rat sciatic nerve healing.
Collapse
Affiliation(s)
- Miroslav Gjurasin
- Department of Pharmacology, Medical Faculty, University of Zagreb Medical School, Salata 11, POB 916, 10000 Zagreb, Croatia
| | | | | | | | | | | | | | | | | | | |
Collapse
|
|
26
|
Anderson G, Noorian AR, Taylor G, Anitha M, Bernhard D, Srinivasan S, Greene JG. Loss of enteric dopaminergic neurons and associated changes in colon motility in an MPTP mouse model of Parkinson's disease. Exp Neurol 2007; 207:4-12. [PMID: 17586496 PMCID: PMC2277100 DOI: 10.1016/j.expneurol.2007.05.010] [Citation(s) in RCA: 174] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2007] [Revised: 05/04/2007] [Accepted: 05/12/2007] [Indexed: 12/14/2022]
Abstract
Gastrointestinal (GI) dysfunction is the most common non-motor symptom of Parkinson's disease (PD). Symptoms of GI dysmotility include early satiety and nausea from delayed gastric emptying, bloating from poor small bowel coordination, and constipation and defecatory dysfunction from impaired colonic transit. Understanding the pathophysiology and treatment of these symptoms in PD patients has been hampered by the lack of investigation into GI symptoms and pathology in PD animal models. We report that the prototypical parkinsonian neurotoxin, MPTP (1-methyl 4-phenyl 1,2,3,6-tetrahydropyridine), is a selective dopamine neuron toxin in the enteric nervous system (ENS). When examined 10 days after treatment, there was a 40% reduction of dopamine neurons in the ENS of C57Bl/6 mice administered MPTP (60 mg/kg). There were no differences in the density of cholinergic or nitric oxide neurons. Electrophysiological recording of neural-mediated muscle contraction in isolated colon from MPTP-treated animals confirmed a relaxation defect associated with dopaminergic degeneration. Behaviorally, MPTP induced a transient increase in colon motility, but no changes in gastric emptying or small intestine transit. These results provide the first comprehensive assessment of gastrointestinal pathophysiology in an animal model of PD. They provide insight into the impact of dopaminergic dysfunction on gastrointestinal motility and a benchmark for assessment of other PD model systems.
Collapse
Affiliation(s)
- Grant Anderson
- Department of Neurology, Emory University School of Medicine, Atlanta, GA 30322, USA
| | | | | | | | | | | | | |
Collapse
|
|
27
|
Dobric I, Drvis P, Petrovic I, Shejbal D, Brcic L, Blagaic AB, Batelja L, Sever M, Kokic N, Tonkic A, Zoricic I, Mise S, Staresinic M, Radic B, Jakir A, Babel J, Ilic S, Vuksic T, Jelic I, Anic T, Seiwerth S, Sikiric P. Prolonged esophagitis after primary dysfunction of the pyloric sphincter in the rat and therapeutic potential of the gastric pentadecapeptide BPC 157. J Pharmacol Sci 2007; 104:7-18. [PMID: 17452811 DOI: 10.1254/jphs.fp0061322] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
Seven or fourteen days or twelve months after suturing one tube into the pyloric sphincter (removed by peristalsis by the seventh day), rats exhibit prolonged esophagitis with a constantly lowered pressure not only in the pyloric, but also in the lower esophageal sphincter and a failure of both sphincters. Throughout the esophagitis experiment, gastric pentadecapeptide BPC 157 (PL 14736) is given intraperitoneally once a day (10 microg/kg, 10 ng/kg, last application 24 h before assessment), or continuously in drinking water at 0.16 microg/ml, 0.16 ng/ml (12 ml/rat per day), or directly into the stomach 5 min before pressure assessment (a water manometer connected to the drainage port of a Foley catheter implanted into the stomach either through an esophageal or duodenal incision). This treatment alleviates i) the esophagitis (macroscopically and microscopically, at either region or interval), ii) the pressure in the pyloric sphincter, and iii) the pressure in the lower esophageal sphincter (cmH2O). In the normal rats it increases lower esophageal sphincter pressure, but decreases the pyloric sphincter pressure. Ranitidine, given using the same protocol (50 mg/kg, intraperitoneally, once daily; 0.83 mg/ml in drinking water; 50 mg/kg directly into the stomach) does not have an effect in either rats with esophagitis or in normal rats.
Collapse
Affiliation(s)
- Ivan Dobric
- Department of Pharmacology, Medical School, University of Zagreb, Croatia
| | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
28
|
Petrovic I, Dobric I, Drvis P, Shejbal D, Brcic L, Blagaic AB, Batelja L, Kokic N, Tonkic A, Mise S, Baotic T, Staresinic M, Radic B, Jakir A, Vuksic T, Anic T, Seiwerth S, Sikiric P. An experimental model of prolonged esophagitis with sphincter failure in the rat and the therapeutic potential of gastric pentadecapeptide BPC 157. J Pharmacol Sci 2007; 102:269-77. [PMID: 17116974 DOI: 10.1254/jphs.fp0060070] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
We report a simple novel rat model that combines prolonged esophagitis and parallel sphincters failure. The anti-ulcer gastric pentadecapeptide BPC 157, which was found to be stable in gastric juice, and is being evaluated in inflammatory bowel disease trials, is an anti-esophagitis therapy that recovers failed sphincters. Twelve or twenty months after the initial challenge (tubes sutured into sphincters for one week and then spontaneously removed by peristalsis), rats exhibit prolonged esophagitis (confluent hemorrhagic and yellowish lesions, thinner epithelium and superficial corneal layer, with stratification derangement); constantly lowered pressure of both sphincters (assessed by using a water manometer connected to the drainage port of a Foley catheter implanted into the stomach either through esophageal or duodenal incision); and both lower esophageal and pyloric sphincter failure. Throughout the esophagitis experiment, BPC 157 was given at either 10 micro g/kg, i.p., once a day (last application 24 h before assessment) or alternatively, it was given continuously in drinking water at 0.16 micro g/ml (12 ml/rat). This treatment recovers i) esophagitis (macroscopically and microscopically, at either region or investigated time period) and ii) pressure in both sphincters (cmH2O). In addition, BPC 157 (10 micro g/kg) or saline (1 ml/rat, 5 ml/kg) was specifically given directly into the stomach; pressure assessment was performed at 5 min thereafter. The effect of BPC 157 is specific because in normal rats, it increases lower esophageal sphincter-pressure, but decreases pyloric sphincter-pressure. Ranitidine, given as the standard drug using the same protocol (50 mg/kg, i.p., once daily; 0.83 mg/ml in drinking water; or 50 mg/kg directly into the stomach) had no effect.
Collapse
Affiliation(s)
- Igor Petrovic
- Department of Pharmacology, Medical Faculty, University of Zagreb, Zagreb, Croatia
| | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
29
|
Boban Blagaic A, Blagaic V, Mirt M, Jelovac N, Dodig G, Rucman R, Petek M, Turkovic B, Anic T, Dubovecak M, Staresinic M, Seiwerth S, Sikiric P. Gastric pentadecapeptide BPC 157 effective against serotonin syndrome in rats. Eur J Pharmacol 2005; 512:173-9. [PMID: 15840402 DOI: 10.1016/j.ejphar.2005.02.033] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2004] [Revised: 02/17/2005] [Accepted: 02/22/2005] [Indexed: 10/25/2022]
Abstract
Serotonin syndrome commonly follows irreversible monoamine oxidase (MAO)-inhibition and subsequent serotonin (5-HT) substrate (in rats with fore paw treading, hind limbs abduction, wet dog shake, hypothermia followed by hyperthermia). A stable gastric pentadecapeptide BPC 157 with very safe profile (inflammatory bowel disease clinical phase II, PL-10, PLD-116, PL-14736, Pliva) reduced the duration of immobility to a greater extent than imipramine, and, given peripherally, has region specific influence on brain 5-HT synthesis (alpha-[14C]methyl-L-tryptophan autoradiographic measurements) in rats, different from any other serotonergic drug. Thereby, we investigate this peptide (10 microg, 10 ng, 10 pg/kg i.p.) in (i) full serotonin syndrome in rat combining pargyline (irreversible MAO-inhibition; 75 mg/kg i.p.) and subsequent L-tryptophan (5-HT precursor; 100 mg/kg i.p.; BPC 157 as a co-treatment), or (ii, iii) using pargyline or L-tryptophan given separately, as a serotonin-substrate with (ii) pargyline (BPC 157 as a 15-min posttreatment) or as a potential serotonin syndrome inductor with (iii) L-tryptophan (BPC 157 as a 15 min-pretreatment). In all experiments, gastric pentadecapeptide BPC 157 contrasts with serotonin-syndrome either (i) presentation (i.e., particularly counteracted) or (ii) initiation (i.e., neither a serotonin substrate (counteraction of pargyline), nor an inductor for serotonin syndrome (no influence on L-tryptophan challenge)). Indicatively, severe serotonin syndrome in pargyline + L-tryptophan rats is considerably inhibited even by lower pentadecapeptide BPC 157 doses regimens (particularly disturbances such as hyperthermia and wet dog shake thought to be related to stimulation of 5-HT2A receptors), while the highest pentadecapeptide dose counteracts mild disturbances present in pargyline rats (mild hypothermia, feeble hind limbs abduction). Thereby, in severe serotonin syndrome, gastric pentadecapeptide BPC 157 (alone, no behavioral or temperature effect) has a beneficial activity, which is likely, particular, and mostly related to a rather specific counteraction of 5-HT2A receptors phenomena.
Collapse
Affiliation(s)
- Alenka Boban Blagaic
- Department of Pharmacology, Medical Faculty, University of Zagreb, Salata 11, POB 916, 10000 Zagreb, Croatia
| | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
30
|
Blagaic AB, Blagaic V, Romic Z, Sikiric P. The influence of gastric pentadecapeptide BPC 157 on acute and chronic ethanol administration in mice. Eur J Pharmacol 2005; 499:285-90. [PMID: 15381050 DOI: 10.1016/j.ejphar.2004.07.112] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2004] [Revised: 07/23/2004] [Accepted: 07/30/2004] [Indexed: 11/25/2022]
Abstract
The stable gastric pentadecapeptide BPC 157 (GEPPPGKPADDAGLV, M.W.1419), which was promising in inflammatory bowel disease (PL-10, PLD-116, PL-14736, Pliva) trials, protects against both acute and chronic alcohol-induced lesions in stomach and liver, but also, given peripherally, affects various centrally mediated disturbances. Now, in male NMRI mice BPC 157 (10 pg intraperitoneally, 10 ng and 10 microg, intraperitoneally or intragastrically) (i) strongly opposed acute alcohol (4 g/kg intraperitoneally) intoxication (i.e., quickly produced and sustained anesthesia, hypothermia, increased ethanol blood values, 25% fatality, 90-min assessment period) given before or after ethanol, and (ii) when given after abrupt cessation of ethanol (at 0 or 3 or 7 h withdrawal time), attenuated withdrawal (assessed through 24 hours) after 20%-alcohol drinking (7.6 g/kg) through 13 days, with provocation on the 14th day.
Collapse
Affiliation(s)
- Alenka Boban Blagaic
- Department of Pharmacology Medical Faculty University of Zagreb, Salata 11, P.O. Box 916, 10000 Zagreb, Croatia
| | | | | | | |
Collapse
|
|
31
|
Tohyama Y, Sikirić P, Diksic M. Effects of pentadecapeptide BPC157 on regional serotonin synthesis in the rat brain: alpha-methyl-L-tryptophan autoradiographic measurements. Life Sci 2004; 76:345-57. [PMID: 15531385 DOI: 10.1016/j.lfs.2004.08.010] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2004] [Accepted: 08/11/2004] [Indexed: 11/17/2022]
Abstract
A novel pentadecapeptide, BPC157, was recently reported to have a large spectrum of in vivo activities, from anti-ulcer to central action on the brain dopaminergic system. The mechanisms of these actions are not well understood. In this study, the evaluation of the effects of acute and repeated administration of BPC157 on serotonin (5-HT) synthesis in the rat brain is reported. The alpha-[14C]methyl-L-tryptophan (alpha-MTrp) autoradiographic method was used to measure regional 5-HT synthesis rates. In the first series of experiments, a single dose treatment of BPC157 (10 microg/kg) administered intraperitoneally 40 min before the alpha-MTrp tracer injection significantly reduced the regional rate of 5-HT synthesis in the dorsal thalamus, hippocampus, lateral geniculate body and hypothalamus. 5-HT synthesis rates in the substantia nigra reticulate and medial anterior olfactory nucleus in BPC157 treated rats were significantly higher than in the control rats. No significant change in the synthesis rate was observed in the raphe nuclei. In the second series of experiments, following a 7-day treatment with BPC157 (10 microg/kg; s.c.), a significant reduction in the 5-HT synthesis rate was observed in the dorsal raphe nucleus, and significant increases were observed in the substantia nigra, lateral caudate, accumbens nucleus and superior olive. This data suggests that BPC157, a gut peptide, influences brain 5-HT synthesis in rats, but we cannot determine, from this data, the mechanism of this action.
Collapse
Affiliation(s)
- Y Tohyama
- Cone Neurosurgical Research Laboratory, Department of Neurology and Neurosurgery, and Montreal Neurological Institute, McGill University, 3801 University Street, Montreal, Quebec, Canada H3A 2B4
| | | | | |
Collapse
|
|
32
|
Xue XC, Wu YJ, Gao MT, Li WG, Zhao N, Wang ZL, Bao CJ, Yan Z, Zhang YQ. Protective effects of pentadecapeptide BPC 157 on gastric ulcer in rats. World J Gastroenterol 2004; 10:1032-6. [PMID: 15052688 PMCID: PMC4717094 DOI: 10.3748/wjg.v10.i7.1032] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
AIM: To investigate the protective effects of gastric pentadecapeptide BPC 157 on acute and chronic gastric ulcers in rats and to compare the results in therapy of human gastric ulcers by different administration methods.
METHODS: Gastric pentadecapeptide BPC 157 was administered (initial single or continuous administration) into rats either intragastrically or intramuscularly before (induced acute gastric ulcer) or after (induced chronic gastric ulcer) the applications of inducing agents, and each animal was sacrificed to observe the protective effects of BPC 157 on gastric ulcers.
RESULTS: Both intramuscular (im) and intragastric (ig) administration of BPC 157 could apparently reduce the ulcer area and accelerate the healing of induced ulcer in different models and the effect of im administered BPC 157 was better than that of ig. The rats treated with higher dosages (400 ng/kg, 800 ng/kg) of BPC 157 (im and ig) showed significantly less lesion (P < 0.01 vs excipient or saline control), the inhibition ratio of ulcer formation varied between 45.7% and 65.6%, from all measurements except 400 ng/kg BPC 157 in pylorus ligation induced model (P < 0.05), in which the inhibition rate was 54.2%. When im administered (800 ng/kg BPC 157) in three models, the inhibition ratio of ulcer formation was 65.5%, 65.6% and 59.9%, respectively, which was better than that of famotidine (its inhibition rate was 60.8%, 57.2% and 34.3%, respectively). Continuous application of BPC 157 (in chronic acetate induced gastric ulcer) could accelerate rebuilding of glandular epithelium and formation of granulation tissue (P < 0.05 at 200 ng/kg and P < 0.01 at 400 ng/kg and 800 ng/kg vs excipient or saline control).
CONCLUSION: Both im and ig administered gastric pentadecapeptide BPC 157 can apparently ameliorate acute gastric ulcer in rats and antagonize the protracted effect of acetate challenge on chronic ulcer. The effect of im administration of BPC 157 is better than that of ig, and the effective dosage of the former is lower than that of the latter.
Collapse
Affiliation(s)
- Xiao-Chang Xue
- Biotechnology Centre, Fourth Military Medical University, 169 West Changle Road, Xi'an 710032, Shaanxi Province, China.
| | | | | | | | | | | | | | | | | |
Collapse
|
|
33
|
Sedelis M, Schwarting RK, Huston JP. Behavioral phenotyping of the MPTP mouse model of Parkinson's disease. Behav Brain Res 2001; 125:109-25. [PMID: 11682102 DOI: 10.1016/s0166-4328(01)00309-6] [Citation(s) in RCA: 323] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
Abstract
In mice, the systemical or intracranial application of the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) can lead to severe damage to the nigrostriatal dopaminergic system. This can result in a variety of symptoms concerning motor control resembling those in human Parkinson's disease, such as akinesia, rigidity, tremor, gait and posture disturbances. The aim of this work is to review a variety of behavioral paradigms for these and other symptoms, which have been used to characterize behavioral changes in mice after MPTP treatment. Main results are summarized, and general influential factors as well as potential problems in the experimental procedures are discussed, which should be taken into account when conducting behavioral analyses in mice with parkinsonian symptoms. Since there is reliable evidence (e.g. from strain comparisons) that the susceptibility of the nigrostriatal pathway to neurodegeneration is probably genetically influenced, relevant genes can be expected to be identified in the future. Therefore, the points discussed here will be useful not only for further applications in the MPTP mouse model, but also more generally for the behavioral characterization of future mouse models of PD, e.g. mice with a manipulation of genes relevant to the function of the basal ganglia.
Collapse
Affiliation(s)
- M Sedelis
- Institute of Physiological Psychology I and Center for Biological and Medical Research, Heinrich-Heine University of Düsseldorf, Universitätsstrasse 1, 40225 Düsseldorf, Germany.
| | | | | |
Collapse
|