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Józwiak M, Bauer M, Kamysz W, Kleczkowska P. Multifunctionality and Possible Medical Application of the BPC 157 Peptide-Literature and Patent Review. Pharmaceuticals (Basel) 2025; 18:185. [PMID: 40005999 PMCID: PMC11859134 DOI: 10.3390/ph18020185] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2025] [Revised: 01/23/2025] [Accepted: 01/28/2025] [Indexed: 02/27/2025] Open
Abstract
BPC 157, known as the "Body Protection Compound", is a pentadecapeptide isolated from human gastric juice that demonstrated its pleiotropic beneficial effects in various preclinical models mimicking medical conditions, such as tissue injury, inflammatory bowel disease, or even CNS disorders. Unlike many other drugs, BPC 157 has a desirable safety profile, since only a few side effects have been reported following its administration. Nevertheless, this compound was temporarily banned by the World Anti-Doping Agency (WADA) in 2022 (it is not currently listed as banned by the WADA). However, it has not been approved for use in standard medicine by the FDA and other global regulatory authorities due to the absence of sufficient and comprehensive clinical studies confirming its health benefits in humans. In this review, we summarize information on the biological activities of BPC 157, with particular reference to its mechanism of action and probable toxicity. This generated the attention of experts, as BPC 157 has been offered for sale on many websites. We also present recent interest in BPC 157 as reflected in a number of patent applications and granted patents.
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Affiliation(s)
- Michalina Józwiak
- Maria Sklodowska-Curie Medical Academy in Warsaw, 03-411 Warsaw, Poland;
| | - Marta Bauer
- Department of Analytical Chemistry, Faculty of Pharmacy, Medical University of Gdansk, 80-416 Gdansk, Poland
| | - Wojciech Kamysz
- Department of Inorganic Chemistry, Faculty of Pharmacy, Medical University of Gdansk, 80-416 Gdansk, Poland;
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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.
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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
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3
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Tepes M, Krezic I, Vranes H, Smoday IM, Kalogjera L, Zizek H, Vukovic V, Oroz K, Kovac KK, Madzar Z, Rakic M, Miskic B, Sikiric S, Barisic I, Strbe S, Antunovic M, Novosel L, Kavelj I, Vlainic J, Dobric I, Staresinic M, Skrtic A, Seiwerth S, Blagaic AB, Sikiric P. Stable Gastric Pentadecapeptide BPC 157 Therapy: Effect on Reperfusion Following Maintained Intra-Abdominal Hypertension (Grade III and IV) in Rats. Pharmaceuticals (Basel) 2023; 16:1554. [PMID: 38004420 PMCID: PMC10675657 DOI: 10.3390/ph16111554] [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: 09/22/2023] [Revised: 10/20/2023] [Accepted: 10/27/2023] [Indexed: 11/26/2023] Open
Abstract
Given in reperfusion, the use of stable gastric pentadecapeptide BPC 157 is an effective therapy in rats. It strongly counteracted, as a whole, decompression/reperfusion-induced occlusion/occlusion-like syndrome following the worst circumstances of acute abdominal compartment and intra-abdominal hypertension, grade III and grade IV, as well as compression/ischemia-occlusion/occlusion-like syndrome. Before decompression (calvariectomy, laparotomy), rats had long-lasting severe intra-abdominal hypertension, grade III (25 mmHg/60 min) (i) and grade IV (30 mmHg/30 min; 40 mmHg/30 min) (ii/iii), and severe occlusion/occlusion-like syndrome. Further worsening was caused by reperfusion for 60 min (i) or 30 min (ii/iii). Severe vascular and multiorgan failure (brain, heart, liver, kidney, and gastrointestinal lesions), widespread thrombosis (peripherally and centrally) severe arrhythmias, intracranial (superior sagittal sinus) hypertension, portal and caval hypertension, and aortal hypotension were aggravated. Contrarily, BPC 157 therapy (10 µg/kg, 10 ng/kg sc) given at 3 min reperfusion times eliminated/attenuated venous hypertension (intracranial (superior sagittal sinus), portal, and caval) and aortal hypotension and counteracted the increases in organ lesions and malondialdehyde values (blood ˃ heart, lungs, liver, kidney ˃ brain, gastrointestinal tract). Vascular recovery promptly occurred (i.e., congested inferior caval and superior mesenteric veins reversed to the normal vessel presentation, the collapsed azygos vein reversed to a fully functioning state, the inferior caval vein-superior caval vein shunt was recovered, and direct blood delivery returned). BPC 157 therapy almost annihilated thrombosis and hemorrhage (i.e., intracerebral hemorrhage) as proof of the counteracted general stasis and Virchow triad circumstances and reorganized blood flow. In conclusion, decompression/reperfusion-induced occlusion/occlusion-like syndrome counteracted by BPC 157 therapy in rats is likely for translation in patients. It is noteworthy that by rapidly counteracting the reperfusion course, it also reverses previous ischemia-course lesions, thus inducing complete recovery.
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Affiliation(s)
- Marijan Tepes
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (M.T.); (I.K.); (H.V.); (I.M.S.); (L.K.); (H.Z.); (V.V.); (K.O.); (K.K.K.); (Z.M.); (I.B.); (S.S.); (L.N.); (I.K.); (A.B.B.)
- Department of Clinical Medicine, Faculty of Dental Medicine and Health Osijek, 31000 Osijek, Croatia;
- PhD Program Translational Research in Biomedicine-TRIBE, School of Medicine, University of Split, 21000 Split, Croatia
| | - Ivan Krezic
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (M.T.); (I.K.); (H.V.); (I.M.S.); (L.K.); (H.Z.); (V.V.); (K.O.); (K.K.K.); (Z.M.); (I.B.); (S.S.); (L.N.); (I.K.); (A.B.B.)
| | - Hrvoje Vranes
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (M.T.); (I.K.); (H.V.); (I.M.S.); (L.K.); (H.Z.); (V.V.); (K.O.); (K.K.K.); (Z.M.); (I.B.); (S.S.); (L.N.); (I.K.); (A.B.B.)
| | - Ivan Maria Smoday
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (M.T.); (I.K.); (H.V.); (I.M.S.); (L.K.); (H.Z.); (V.V.); (K.O.); (K.K.K.); (Z.M.); (I.B.); (S.S.); (L.N.); (I.K.); (A.B.B.)
| | - Luka Kalogjera
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (M.T.); (I.K.); (H.V.); (I.M.S.); (L.K.); (H.Z.); (V.V.); (K.O.); (K.K.K.); (Z.M.); (I.B.); (S.S.); (L.N.); (I.K.); (A.B.B.)
| | - Helena Zizek
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (M.T.); (I.K.); (H.V.); (I.M.S.); (L.K.); (H.Z.); (V.V.); (K.O.); (K.K.K.); (Z.M.); (I.B.); (S.S.); (L.N.); (I.K.); (A.B.B.)
| | - Vlasta Vukovic
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (M.T.); (I.K.); (H.V.); (I.M.S.); (L.K.); (H.Z.); (V.V.); (K.O.); (K.K.K.); (Z.M.); (I.B.); (S.S.); (L.N.); (I.K.); (A.B.B.)
| | - Katarina Oroz
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (M.T.); (I.K.); (H.V.); (I.M.S.); (L.K.); (H.Z.); (V.V.); (K.O.); (K.K.K.); (Z.M.); (I.B.); (S.S.); (L.N.); (I.K.); (A.B.B.)
| | - Katarina Kasnik Kovac
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (M.T.); (I.K.); (H.V.); (I.M.S.); (L.K.); (H.Z.); (V.V.); (K.O.); (K.K.K.); (Z.M.); (I.B.); (S.S.); (L.N.); (I.K.); (A.B.B.)
| | - Zrinko Madzar
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (M.T.); (I.K.); (H.V.); (I.M.S.); (L.K.); (H.Z.); (V.V.); (K.O.); (K.K.K.); (Z.M.); (I.B.); (S.S.); (L.N.); (I.K.); (A.B.B.)
| | - Mislav Rakic
- Department of Abdominal Surgery, Clinical Hospital Dubrava, 10040 Zagreb, Croatia;
| | - Blazenka Miskic
- Department of Clinical Medicine, Faculty of Dental Medicine and Health Osijek, 31000 Osijek, Croatia;
| | - Suncana Sikiric
- Department of Pathology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (S.S.); (S.S.)
| | - Ivan Barisic
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (M.T.); (I.K.); (H.V.); (I.M.S.); (L.K.); (H.Z.); (V.V.); (K.O.); (K.K.K.); (Z.M.); (I.B.); (S.S.); (L.N.); (I.K.); (A.B.B.)
| | - Sanja Strbe
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (M.T.); (I.K.); (H.V.); (I.M.S.); (L.K.); (H.Z.); (V.V.); (K.O.); (K.K.K.); (Z.M.); (I.B.); (S.S.); (L.N.); (I.K.); (A.B.B.)
| | - Marko Antunovic
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (M.T.); (I.K.); (H.V.); (I.M.S.); (L.K.); (H.Z.); (V.V.); (K.O.); (K.K.K.); (Z.M.); (I.B.); (S.S.); (L.N.); (I.K.); (A.B.B.)
| | - Luka Novosel
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (M.T.); (I.K.); (H.V.); (I.M.S.); (L.K.); (H.Z.); (V.V.); (K.O.); (K.K.K.); (Z.M.); (I.B.); (S.S.); (L.N.); (I.K.); (A.B.B.)
| | - Ivana Kavelj
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (M.T.); (I.K.); (H.V.); (I.M.S.); (L.K.); (H.Z.); (V.V.); (K.O.); (K.K.K.); (Z.M.); (I.B.); (S.S.); (L.N.); (I.K.); (A.B.B.)
| | - Josipa Vlainic
- Laboratory for Advanced Genomics, Division of Molecular Medicine, Institute 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; (S.S.); (S.S.)
| | - Sven Seiwerth
- Department of Pathology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (S.S.); (S.S.)
| | - Alenka Boban Blagaic
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (M.T.); (I.K.); (H.V.); (I.M.S.); (L.K.); (H.Z.); (V.V.); (K.O.); (K.K.K.); (Z.M.); (I.B.); (S.S.); (L.N.); (I.K.); (A.B.B.)
| | - Predrag Sikiric
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (M.T.); (I.K.); (H.V.); (I.M.S.); (L.K.); (H.Z.); (V.V.); (K.O.); (K.K.K.); (Z.M.); (I.B.); (S.S.); (L.N.); (I.K.); (A.B.B.)
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Kalogjera L, Krezic I, Smoday IM, Vranes H, Zizek H, Yago H, Oroz K, Vukovic V, Kavelj I, Novosel L, Zubcic S, Barisic I, Beketic Oreskovic L, Strbe S, Sever M, Sjekavica I, Skrtic A, Boban Blagaic A, Seiwerth S, Sikiric P. Stomach perforation-induced general occlusion/occlusion-like syndrome and stable gastric pentadecapeptide BPC 157 therapy effect. World J Gastroenterol 2023; 29:4289-4316. [PMID: 37545637 PMCID: PMC10401663 DOI: 10.3748/wjg.v29.i27.4289] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/19/2023] [Revised: 06/01/2023] [Accepted: 06/19/2023] [Indexed: 07/13/2023] Open
Abstract
BACKGROUND Using rat stomach perforation as a prototypic direct lesion applied in cytoprotection research, we focused on the first demonstration of the severe occlusion/ occlusion-like syndrome induced by stomach perforation. The revealed stomach-induced occlusion/occlusion-like syndrome corresponds to the previously described occlusion/occlusion-like syndromes in rats suffering multicausal pathology and shared severe vascular and multiorgan failure. This general point was particularly reviewed. As in all the described occlusion/occlusion-like syndromes with permanent occlusion of major vessels, peripheral and central, and other similar noxious procedures that severely affect endothelium function, the stable gastric pentadecapeptide BPC 157 was resolving therapy.
AIM To reveal the stomach perforation-induced general occlusion/occlusion-like syndrome and BPC 157 therapy effect.
METHODS The procedure included deeply anesthetized rats, complete calvariectomy, laparotomy at 15 min thereafter, and stomach perforation to rapidly induce vascular and multiorgan failure occlusion/occlusion-like syndrome. At 5 min post-perforation time, rats received therapy [BPC 157 (10 µg or 10 ng/kg) or saline (5 mL/kg, 1 mL/rat) (controls)] into the perforated defect in the stomach). Sacrifice was at 15 min or 60 min post-perforation time. Assessment (gross and microscopy; volume) included: Brain swelling, peripheral vessels (azygos vein, superior mesenteric vein, portal vein, inferior caval vein) and heart, other organs lesions (i.e., stomach, defect closing or widening); superior sagittal sinus, and peripherally the portal vein, inferior caval vein, and abdominal aorta blood pressures and clots; electrocardiograms; and bleeding time from the perforation(s).
RESULTS BPC 157 beneficial effects accord with those noted before in the healing of the perforated defect (raised vessel presentation; less bleeding, defect contraction) and occlusion/occlusion-like syndromes counteraction. BPC 157 therapy (into the perforated defect), induced immediate shrinking and contraction of the whole stomach (unlike considerable enlargement by saline application). Accordingly, BPC 157 therapy induced direct blood delivery via the azygos vein, and attenuated/eliminated the intracranial (superior sagittal sinus), portal and caval hypertension, and aortal hypotension. Thrombosis, peripherally (inferior caval vein, portal vein, abdominal aorta) and centrally (superior sagittal sinus) BPC 157 therapy markedly reduced/annihilated. Severe lesions in the brain (swelling, hemorrhage), heart (congestion and arrhythmias), lung (hemorrhage and congestion), and marked congestion in the liver, kidney, and gastrointestinal tract were markedly reduced.
CONCLUSION We revealed stomach perforation as a severe occlusion/occlusion-like syndrome, peripherally and centrally, and rapid counteraction by BPC 157 therapy. Thereby, further BPC 157 therapy may be warranted.
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Affiliation(s)
- Luka Kalogjera
- Department of Pharmacology, School of Medicine, Zagreb 10000, Croatia
| | - Ivan Krezic
- Department of Pharmacology, School of Medicine, Zagreb 10000, Croatia
| | - Ivan Maria Smoday
- Department of Pharmacology, School of Medicine, Zagreb 10000, Croatia
| | - Hrvoje Vranes
- Department of Pharmacology, School of Medicine, Zagreb 10000, Croatia
| | - Helena Zizek
- Department of Pharmacology, School of Medicine, Zagreb 10000, Croatia
| | - Haidi Yago
- Department of Pharmacology, School of Medicine, Zagreb 10000, Croatia
| | - Katarina Oroz
- Department of Pharmacology, School of Medicine, Zagreb 10000, Croatia
| | - Vlasta Vukovic
- Department of Pharmacology, School of Medicine, Zagreb 10000, Croatia
| | - Ivana Kavelj
- Department of Pharmacology, School of Medicine, Zagreb 10000, Croatia
| | - Luka Novosel
- Department of Pharmacology, School of Medicine, Zagreb 10000, Croatia
| | - Slavica Zubcic
- Department of Pharmacology, School of Medicine, Zagreb 10000, Croatia
| | - Ivan Barisic
- Department of Pharmacology, School of Medicine, Zagreb 10000, Croatia
| | - Lidija Beketic Oreskovic
- Division of Oncology and Radiotherapy, University Hospital for Tumors, Sestre milosrdnice University Hospital Centre, Zagreb 10000, Croatia
| | - Sanja Strbe
- Department of Pharmacology, School of Medicine, Zagreb 10000, Croatia
| | - Marko Sever
- Department of Pharmacology, School of Medicine, Zagreb 10000, Croatia
| | - Ivica Sjekavica
- Department of Pharmacology, School of Medicine, Zagreb 10000, Croatia
| | - Anita Skrtic
- Department of Pathology, School of Medicine, Zagreb 10000, Croatia
| | | | - Sven Seiwerth
- Department of Pathology, School of Medicine, Zagreb 10000, Croatia
| | - Predrag Sikiric
- Department of Pharmacology, School of Medicine, Zagreb 10000, Croatia
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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.
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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
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Pentadecapeptide BPC 157 efficiently reduces radiation-induced liver injury and lipid accumulation through Kruppel-like factor 4 upregulation both in vivo and in vitro. Life Sci 2022; 310:121072. [DOI: 10.1016/j.lfs.2022.121072] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2022] [Revised: 10/05/2022] [Accepted: 10/07/2022] [Indexed: 11/06/2022]
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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.
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Smoday IM, Petrovic I, Kalogjera L, Vranes H, Zizek H, Krezic I, Gojkovic S, Skorak I, Hriberski K, Brizic I, Kubat M, Strbe S, Barisic I, Sola M, Lovric E, Lozic M, Boban Blagaic A, Skrtic A, Seiwerth S, Sikiric P. Therapy Effect of the Stable Gastric Pentadecapeptide BPC 157 on Acute Pancreatitis as Vascular Failure-Induced Severe Peripheral and Central Syndrome in Rats. Biomedicines 2022; 10:biomedicines10061299. [PMID: 35740321 PMCID: PMC9220115 DOI: 10.3390/biomedicines10061299] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2022] [Revised: 05/24/2022] [Accepted: 05/27/2022] [Indexed: 12/15/2022] Open
Abstract
We revealed the therapy effect of the stable gastric pentadecapeptide BPC 157 (10 μg/kg, 10 ng/kg ig or po) with specific activation of the collateral rescuing pathways, the azygos vein, on bile duct ligation in particular, and acute pancreatitis as local disturbances (i.e., improved gross and microscopy presentation, decreased amylase level). Additionally, we revealed the therapy’s effect on the acute pancreatitis as vascular failure and multiorgan failure, both peripherally and centrally following “occlusion-like” syndrome, major intoxication (alcohol, lithium), maintained severe intra-abdominal hypertension, and myocardial infarction, or occlusion syndrome, and major vessel occlusion. The application-sacrifice periods were ligation times of 0–30 min, 0–5 h, 0–24 h (cured periods, early regimen) and 4.30 h–5 h, 5 h–24 h (cured periods, delayed regimen). Otherwise, bile duct-ligated rats commonly presented intracranial (superior sagittal sinus), portal and caval hypertension and aortal hypotension, gross brain swelling, hemorrhage and lesions, heart dysfunction, lung lesions, liver and kidney failure, gastrointestinal lesions, and severe arterial and venous thrombosis, peripherally and centrally. Unless antagonized with the key effect of BPC 157 regimens, reversal of the inferior caval and superior mesenteric vein congestion and reversal of the failed azygos vein activated azygos vein-recruited direct delivery to rescue the inferior-superior caval vein pathway; these were all antecedent to acute pancreatitis major lesions (i.e., acinar, fat necrosis, hemorrhage). These lesions appeared in the later period, but were markedly attenuated/eliminated (i.e., hemorrhage) in BPC 157-treated rats. To summarize, while the innate vicious cycle may be peripheral (bile duct ligation), or central (rapidly developed brain disturbances), or peripheral and central, BPC 157 resolved acute pancreatitis and its adjacent syndrome.
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Affiliation(s)
- Ivan Maria Smoday
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (I.M.S.); (L.K.); (H.V.); (H.Z.); (I.K.); (S.G.); (I.S.); (K.H.); (I.B.); (S.S.); (I.B.); (M.S.); (A.B.B.)
| | - Igor Petrovic
- Department of Surgery, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia;
| | - Luka Kalogjera
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (I.M.S.); (L.K.); (H.V.); (H.Z.); (I.K.); (S.G.); (I.S.); (K.H.); (I.B.); (S.S.); (I.B.); (M.S.); (A.B.B.)
| | - Hrvoje Vranes
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (I.M.S.); (L.K.); (H.V.); (H.Z.); (I.K.); (S.G.); (I.S.); (K.H.); (I.B.); (S.S.); (I.B.); (M.S.); (A.B.B.)
| | - Helena Zizek
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (I.M.S.); (L.K.); (H.V.); (H.Z.); (I.K.); (S.G.); (I.S.); (K.H.); (I.B.); (S.S.); (I.B.); (M.S.); (A.B.B.)
| | - Ivan Krezic
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (I.M.S.); (L.K.); (H.V.); (H.Z.); (I.K.); (S.G.); (I.S.); (K.H.); (I.B.); (S.S.); (I.B.); (M.S.); (A.B.B.)
| | - Slaven Gojkovic
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (I.M.S.); (L.K.); (H.V.); (H.Z.); (I.K.); (S.G.); (I.S.); (K.H.); (I.B.); (S.S.); (I.B.); (M.S.); (A.B.B.)
| | - Ivan Skorak
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (I.M.S.); (L.K.); (H.V.); (H.Z.); (I.K.); (S.G.); (I.S.); (K.H.); (I.B.); (S.S.); (I.B.); (M.S.); (A.B.B.)
| | - Klaudija Hriberski
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (I.M.S.); (L.K.); (H.V.); (H.Z.); (I.K.); (S.G.); (I.S.); (K.H.); (I.B.); (S.S.); (I.B.); (M.S.); (A.B.B.)
| | - Ivan Brizic
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (I.M.S.); (L.K.); (H.V.); (H.Z.); (I.K.); (S.G.); (I.S.); (K.H.); (I.B.); (S.S.); (I.B.); (M.S.); (A.B.B.)
| | - Milovan Kubat
- Department of Forensic Medicine and Criminology, School of Medicne, 10000 Zagreb, Croatia;
| | - Sanja Strbe
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (I.M.S.); (L.K.); (H.V.); (H.Z.); (I.K.); (S.G.); (I.S.); (K.H.); (I.B.); (S.S.); (I.B.); (M.S.); (A.B.B.)
| | - Ivan Barisic
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (I.M.S.); (L.K.); (H.V.); (H.Z.); (I.K.); (S.G.); (I.S.); (K.H.); (I.B.); (S.S.); (I.B.); (M.S.); (A.B.B.)
| | - Marija Sola
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (I.M.S.); (L.K.); (H.V.); (H.Z.); (I.K.); (S.G.); (I.S.); (K.H.); (I.B.); (S.S.); (I.B.); (M.S.); (A.B.B.)
| | - Eva Lovric
- Department of Pathology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (E.L.); (S.S.)
| | - Marin Lozic
- Department of Pediatric and Preventive Dentistry, School of Dental Medicine, University of Zagreb, 10000 Zagreb, Croatia;
| | - Alenka Boban Blagaic
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (I.M.S.); (L.K.); (H.V.); (H.Z.); (I.K.); (S.G.); (I.S.); (K.H.); (I.B.); (S.S.); (I.B.); (M.S.); (A.B.B.)
| | - Anita Skrtic
- Department of Pathology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (E.L.); (S.S.)
- Correspondence: (A.S.); (P.S.); Tel.: +385-1-4566-980 (A.S.); +385-1-4566-833 (P.S.)
| | - Sven Seiwerth
- Department of Pathology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (E.L.); (S.S.)
| | - Predrag Sikiric
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (I.M.S.); (L.K.); (H.V.); (H.Z.); (I.K.); (S.G.); (I.S.); (K.H.); (I.B.); (S.S.); (I.B.); (M.S.); (A.B.B.)
- Correspondence: (A.S.); (P.S.); Tel.: +385-1-4566-980 (A.S.); +385-1-4566-833 (P.S.)
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Tepes M, Gojkovic S, Krezic I, Zizek H, Vranes H, Madzar Z, Santak G, Batelja L, Milavic M, Sikiric S, Kocman I, Simonji K, Samara M, Knezevic M, Barisic I, Lovric E, Strbe S, Kokot A, Sjekavica I, Kolak T, Skrtic A, Seiwerth S, Boban Blagaic A, Sikiric P. Stable Gastric Pentadecapeptide BPC 157 Therapy for Primary Abdominal Compartment Syndrome in Rats. Front Pharmacol 2021; 12:718147. [PMID: 34966273 PMCID: PMC8710746 DOI: 10.3389/fphar.2021.718147] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2021] [Accepted: 11/17/2021] [Indexed: 12/14/2022] Open
Abstract
Recently, the stable gastric pentadecapeptide BPC 157 was shown to counteract major vessel occlusion syndromes, i.e., peripheral and/or central occlusion, while activating particular collateral pathways. We induced abdominal compartment syndrome (intra-abdominal pressure in thiopental-anesthetized rats at 25 mmHg (60 min), 30 mmHg (30 min), 40 mmHg (30 min), and 50 mmHg (15 min) and in esketamine-anesthetized rats (25 mmHg for 120 min)) as a model of multiple occlusion syndrome. By improving the function of the venous system with BPC 157, we reversed the chain of harmful events. Rats with intra-abdominal hypertension (grade III, grade IV) received BPC 157 (10 µg or 10 ng/kg sc) or saline (5 ml) after 10 min. BPC 157 administration recovered the azygos vein via the inferior–superior caval vein rescue pathway. Additionally, intracranial (superior sagittal sinus), portal, and caval hypertension and aortal hypotension were reduced, as were the grossly congested stomach and major hemorrhagic lesions, brain swelling, venous and arterial thrombosis, congested inferior caval and superior mesenteric veins, and collapsed azygos vein; thus, the failed collateral pathway was fully recovered. Severe ECG disturbances (i.e., severe bradycardia and ST-elevation until asystole) were also reversed. Microscopically, transmural hyperemia of the gastrointestinal tract, intestinal mucosa villi reduction, crypt reduction with focal denudation of superficial epithelia, and large bowel dilatation were all inhibited. In the liver, BPC 157 reduced congestion and severe sinusoid enlargement. In the lung, a normal presentation was observed, with no alveolar membrane focal thickening and no lung congestion or edema, and severe intra-alveolar hemorrhage was absent. Moreover, severe heart congestion, subendocardial infarction, renal hemorrhage, brain edema, hemorrhage, and neural damage were prevented. In conclusion, BPC 157 cured primary abdominal compartment syndrome.
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Affiliation(s)
- Marijan Tepes
- Department of Surgery, General Hospital Nasice, Nasice, Croatia
- Department of Clinical Medicine, Faculty of Dental Medicine and Health Osijek, Osijek, Croatia
- PhD Program Translational Research in Biomedicine—TRIBE, School of Medicine, University of Split, Split, Croatia
- Department of Pharmacology, School of Medicine, University of Zagreb, Zagreb, Croatia
| | - Slaven Gojkovic
- Department of Pharmacology, School of Medicine, University of Zagreb, Zagreb, Croatia
| | - Ivan Krezic
- Department of Pharmacology, School of Medicine, University of Zagreb, Zagreb, Croatia
| | - Helena Zizek
- Department of Pharmacology, School of Medicine, University of Zagreb, Zagreb, Croatia
| | - Hrvoje Vranes
- Department of Pharmacology, School of Medicine, University of Zagreb, Zagreb, Croatia
| | - Zrinko Madzar
- Clinical Department of Surgery, Sestre Milosrdnice University Hospital Center, Zagreb, Croatia
| | - Goran Santak
- Department of Surgery, Faculty of Medicine, University of Osijek, Osijek, Croatia
| | - Lovorka Batelja
- Department of Pathology, School of Medicine, University of Zagreb, Zagreb, Croatia
| | - Marija Milavic
- Department of Pathology, School of Medicine, University of Zagreb, Zagreb, Croatia
| | - Suncana Sikiric
- Department of Pathology, School of Medicine, University of Zagreb, Zagreb, Croatia
| | - Ivica Kocman
- Department of Pharmacology, School of Medicine, University of Zagreb, Zagreb, Croatia
| | - Karol Simonji
- Internal Diseases Clinic, Faculty of Veterinary Medicine Zagreb, Zagreb, Croatia
| | - Mariam Samara
- Department of Pharmacology, School of Medicine, University of Zagreb, Zagreb, Croatia
| | - Mario Knezevic
- Department of Pharmacology, School of Medicine, University of Zagreb, Zagreb, Croatia
| | - Ivan Barisic
- Department of Pharmacology, School of Medicine, University of Zagreb, Zagreb, Croatia
| | - Eva Lovric
- Department of Pathology, School of Medicine, University of Zagreb, Zagreb, Croatia
| | - Sanja Strbe
- Department of Pharmacology, School of Medicine, University of Zagreb, Zagreb, Croatia
| | - Antonio Kokot
- Department of Anatomy and Neuroscience, Faculty of Medicine, J.J. Strossmayer University of Osijek, Osijek, Croatia
| | - Ivica Sjekavica
- Department of Diagnostic and Interventional Radiology, University Hospital Centre, Zagreb, Croatia
| | - Toni Kolak
- Department of Surgery, School of Medicine, University of Zagreb, Zagreb, Croatia
| | - Anita Skrtic
- Department of Pathology, School of Medicine, University of Zagreb, Zagreb, Croatia
- *Correspondence: Predrag Sikiric, ; Anita Skrtic,
| | - Sven Seiwerth
- Department of Pathology, School of Medicine, University of Zagreb, Zagreb, Croatia
| | - Alenka Boban Blagaic
- Department of Pharmacology, School of Medicine, University of Zagreb, Zagreb, Croatia
| | - Predrag Sikiric
- Department of Pharmacology, School of Medicine, University of Zagreb, Zagreb, Croatia
- *Correspondence: Predrag Sikiric, ; Anita Skrtic,
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10
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Deek SA. BPC 157 as Potential Treatment for COVID-19. Med Hypotheses 2021; 158:110736. [PMID: 34798584 PMCID: PMC8575535 DOI: 10.1016/j.mehy.2021.110736] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2021] [Revised: 10/07/2021] [Accepted: 11/03/2021] [Indexed: 02/07/2023]
Abstract
The emergence of coronavirus disease (COVID-19) in China at the end of 2019 has caused a large global outbreak. COVID-19 is largely seen as a thrombotic and vascular disease targeting endothelial cells (ECs) throughout the body that can provoke the breakdown of central vascular functions. This explains the complications and multi-organ failure seen in COVID-19 patients including acute respiratory distress syndrome, cardiovascular complications, liver damage, and neurological damage. Acknowledging the comorbidities and potential organ injuries throughout the course of COVID-19 is therefore crucial in the clinical management of patients. Here we discuss BPC 157, based primarily on animal model data, as a novel agent that can improve the clinical management of COVID-19. BPC 157 is a peptide that has demonstrated anti-inflammatory, cytoprotective, and endothelial-protective effects in different organ systems in different species. BPC 157 activated endothelial nitric oxide synthase (eNOS) is associated with nitric oxide (NO) release, tissue repair and angiomodulatory properties which can lead to improved vascular integrity and immune response, reduced proinflammatory profile, and reduced critical levels of the disease. As a result, discussion of its use as a potential prophylactic and complementary treatment is critical. All examined treatments, although potentiality effective against COVID-19, need either appropriate drug development or clinical trials in humans to be suitable for clinical use.
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Affiliation(s)
- Sarah A Deek
- Department of Civil, Architectural and Environmental Engineering, The University of Texas at Austin, 78712 Austin, TX, USA.
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Gojkovic S, Krezic I, Vranes H, Zizek H, Drmic D, Batelja Vuletic L, Milavic M, Sikiric S, Stilinovic I, Simeon P, Knezevic M, Kolak T, Tepes M, Simonji K, Strbe S, Nikolac Gabaj N, Barisic I, Oreskovic EG, Lovric E, Kokot A, Skrtic A, Boban Blagaic A, Seiwerth S, Sikiric P. Robert's Intragastric Alcohol-Induced Gastric Lesion Model as an Escalated General Peripheral and Central Syndrome, Counteracted by the Stable Gastric Pentadecapeptide BPC 157. Biomedicines 2021; 9:1300. [PMID: 34680419 PMCID: PMC8533388 DOI: 10.3390/biomedicines9101300] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2021] [Revised: 09/12/2021] [Accepted: 09/17/2021] [Indexed: 12/11/2022] Open
Abstract
We redefined Robert's prototypical cytoprotection model, namely the intragastric administration of 96% alcohol in order to generate a general peripheral and central syndrome similar to that which occurs when major central or peripheral veins are occluded in animal models. With this redefinition, we used Robert's model to examine the cytoprotective effects of the stable gastric pentadecapeptide BPC 157. The intragastric administration of alcohol induced gastric lesions, intracranial (superior sagittal sinus) hypertension, severe brain swelling and lesions, portal and vena caval hypertension, aortal hypotension, severe thrombosis, inferior vena cava and superior mesenteric vein congestion, azygos vein failure (as a failed collateral pathway), electrocardiogram disturbances, and heart, lung, liver and kidney lesions. The use of BPC 157 therapy (10 µg/kg or 10 ng/kg given intraperitoneally 1 min after alcohol) counteracted these deficits rapidly. Specifically, BPC 157 reversed brain swelling and superior mesenteric vein and inferior vena caval congestion, and helped the azygos vein to recover, which improved the collateral blood flow pathway. Microscopically, BPC 157 counteracted brain (i.e., intracerebral hemorrhage with degenerative changes of cerebral and cerebellar neurons), heart (acute subendocardial infarct), lung (parenchymal hemorrhage), liver (congestion), kidney (congestion) and gastrointestinal (epithelium loss, hemorrhagic gastritis) lesions. In addition, this may have taken place along with the activation of specific molecular pathways. In conclusion, these findings clarify and extend the theory of cytoprotection, offer an approach to its practical application, and establish BPC 157 as a prospective cytoprotective treatment.
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Affiliation(s)
- Slaven Gojkovic
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (S.G.); (I.K.); (H.V.); (H.Z.); (D.D.); (I.S.); (M.K.); (M.T.); (S.S.); (I.B.); (E.G.O.); (A.B.B.)
| | - Ivan Krezic
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (S.G.); (I.K.); (H.V.); (H.Z.); (D.D.); (I.S.); (M.K.); (M.T.); (S.S.); (I.B.); (E.G.O.); (A.B.B.)
| | - Hrvoje Vranes
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (S.G.); (I.K.); (H.V.); (H.Z.); (D.D.); (I.S.); (M.K.); (M.T.); (S.S.); (I.B.); (E.G.O.); (A.B.B.)
| | - Helena Zizek
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (S.G.); (I.K.); (H.V.); (H.Z.); (D.D.); (I.S.); (M.K.); (M.T.); (S.S.); (I.B.); (E.G.O.); (A.B.B.)
| | - Domagoj Drmic
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (S.G.); (I.K.); (H.V.); (H.Z.); (D.D.); (I.S.); (M.K.); (M.T.); (S.S.); (I.B.); (E.G.O.); (A.B.B.)
| | - Lovorka Batelja Vuletic
- Department of Pathology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (L.B.V.); (M.M.); (S.S.); (E.L.); (A.S.); (S.S.)
| | - Marija Milavic
- Department of Pathology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (L.B.V.); (M.M.); (S.S.); (E.L.); (A.S.); (S.S.)
| | - Suncana Sikiric
- Department of Pathology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (L.B.V.); (M.M.); (S.S.); (E.L.); (A.S.); (S.S.)
| | - Irma Stilinovic
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (S.G.); (I.K.); (H.V.); (H.Z.); (D.D.); (I.S.); (M.K.); (M.T.); (S.S.); (I.B.); (E.G.O.); (A.B.B.)
| | - Paris Simeon
- Department of Endodontics and Restorative Dentistry, School of Dental Medicine, University of Zagreb, 10000 Zagreb, Croatia;
| | - Mario Knezevic
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (S.G.); (I.K.); (H.V.); (H.Z.); (D.D.); (I.S.); (M.K.); (M.T.); (S.S.); (I.B.); (E.G.O.); (A.B.B.)
| | - Toni Kolak
- Department of Surgery, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia;
| | - Marijan Tepes
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (S.G.); (I.K.); (H.V.); (H.Z.); (D.D.); (I.S.); (M.K.); (M.T.); (S.S.); (I.B.); (E.G.O.); (A.B.B.)
| | - Karol Simonji
- Internal Diseases Clinic, Faculty of Veterinary Medicine, University of Zagreb, 10000 Zagreb, Croatia;
| | - Sanja Strbe
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (S.G.); (I.K.); (H.V.); (H.Z.); (D.D.); (I.S.); (M.K.); (M.T.); (S.S.); (I.B.); (E.G.O.); (A.B.B.)
| | - Nora Nikolac Gabaj
- Department of Chemistry, University Clinical Hospital Center “Sestre Milosrdnice”, 10000 Zagreb, Croatia;
| | - Ivan Barisic
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (S.G.); (I.K.); (H.V.); (H.Z.); (D.D.); (I.S.); (M.K.); (M.T.); (S.S.); (I.B.); (E.G.O.); (A.B.B.)
| | - Emma Grace Oreskovic
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (S.G.); (I.K.); (H.V.); (H.Z.); (D.D.); (I.S.); (M.K.); (M.T.); (S.S.); (I.B.); (E.G.O.); (A.B.B.)
| | - Eva Lovric
- Department of Pathology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (L.B.V.); (M.M.); (S.S.); (E.L.); (A.S.); (S.S.)
| | - Antonio Kokot
- Department of Anatomy and Neuroscience, School of Medicine, J.J. Strossmayer University of Osijek, 31000 Osijek, Croatia;
| | - Anita Skrtic
- Department of Pathology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (L.B.V.); (M.M.); (S.S.); (E.L.); (A.S.); (S.S.)
| | - Alenka Boban Blagaic
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (S.G.); (I.K.); (H.V.); (H.Z.); (D.D.); (I.S.); (M.K.); (M.T.); (S.S.); (I.B.); (E.G.O.); (A.B.B.)
| | - Sven Seiwerth
- Department of Pathology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (L.B.V.); (M.M.); (S.S.); (E.L.); (A.S.); (S.S.)
| | - Predrag Sikiric
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (S.G.); (I.K.); (H.V.); (H.Z.); (D.D.); (I.S.); (M.K.); (M.T.); (S.S.); (I.B.); (E.G.O.); (A.B.B.)
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Knezevic M, Gojkovic S, Krezic I, Zizek H, Vranes H, Malekinusic D, Vrdoljak B, Knezevic T, Horvat Pavlov K, Drmic D, Staroveski M, Djuzel A, Rajkovic Z, Kolak T, Lovric E, Milavic M, Sikiric S, Barisic I, Tepes M, Tvrdeic A, Patrlj L, Strbe S, Sola M, Situm A, Kokot A, Boban Blagaic A, Skrtic A, Seiwerth S, Sikiric P. Complex Syndrome of the Complete Occlusion of the End of the Superior Mesenteric Vein, Opposed with the Stable Gastric Pentadecapeptide BPC 157 in Rats. Biomedicines 2021; 9:1029. [PMID: 34440233 PMCID: PMC8394093 DOI: 10.3390/biomedicines9081029] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2021] [Revised: 08/08/2021] [Accepted: 08/10/2021] [Indexed: 12/11/2022] Open
Abstract
Background. Gastric pentadecapeptide BPC 157 therapy in rats compensated irremovable occlusion of various vessels and counteracted the consequent multiorgan dysfunction syndromes by activation of the corresponding collateral bypassing loops. Thus, we used BPC 157 therapy against the irremovable occlusion of the end of the superior mesenteric vein. Methods. Assessments, for 30 min (gross recording, venography, ECG, pressure, microscopy, biochemistry, and oxidative stress) include the portal and caval hypertension, aortal hypotension, and centrally, the superior sagittal sinus hypertension, systemic arterial and venous thrombosis, ECG disturbances, MDA-tissue increase, and heart, lung, liver, kidney and gastrointestinal tract, in particular, and brain (cortex (cerebral, cerebellar), hypothalamus/thalamus, hippocampus) lesions. Rats received BPC 157 medication (10 µg/kg, 10 ng/kg) intraperitoneally at 1 or 15 min ligation time. Results. BPC 157 rapidly activated the superior mesenteric vein-inferior anterior pancreati-coduodenal vein-superior anterior pancreaticoduodenal vein-pyloric vein-portal vein pathway, reestablished superior mesenteric vein and portal vein connection and reestablished blood flow. Simultaneously, toward inferior caval vein, an additional pathway appears via the inferior mesenteric vein united with the middle colic vein, throughout its left colic branch to ascertain alternative bypassing blood flow. Consequently, BPC 157 acts peripherally and centrally, and counteracted the intracranial (superior sagittal sinus), portal and caval hypertension, aortal hypotension, ECG disturbances attenuated, abolished progressing venous and arterial thrombosis. Additionally, BPC 157 counteracted multiorgan dysfunction syndrome, heart, lung, liver, kidney and gastrointestinal tract, and brain lesions, and oxidative stress in tissues. Conclusion. BPC 157 therapy may be specific management also for the superior mesenteric vein injuries.
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Affiliation(s)
- Mario Knezevic
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (M.K.); (S.G.); (I.K.); (H.Z.); (H.V.); (D.M.); (B.V.); (T.K.); (D.D.); (M.S.); (A.D.); (T.K.); (I.B.); (M.T.); (A.T.); (L.P.); (S.S.); (M.S.); (A.S.); (A.K.); (A.B.B.)
| | - Slaven Gojkovic
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (M.K.); (S.G.); (I.K.); (H.Z.); (H.V.); (D.M.); (B.V.); (T.K.); (D.D.); (M.S.); (A.D.); (T.K.); (I.B.); (M.T.); (A.T.); (L.P.); (S.S.); (M.S.); (A.S.); (A.K.); (A.B.B.)
| | - Ivan Krezic
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (M.K.); (S.G.); (I.K.); (H.Z.); (H.V.); (D.M.); (B.V.); (T.K.); (D.D.); (M.S.); (A.D.); (T.K.); (I.B.); (M.T.); (A.T.); (L.P.); (S.S.); (M.S.); (A.S.); (A.K.); (A.B.B.)
| | - Helena Zizek
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (M.K.); (S.G.); (I.K.); (H.Z.); (H.V.); (D.M.); (B.V.); (T.K.); (D.D.); (M.S.); (A.D.); (T.K.); (I.B.); (M.T.); (A.T.); (L.P.); (S.S.); (M.S.); (A.S.); (A.K.); (A.B.B.)
| | - Hrvoje Vranes
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (M.K.); (S.G.); (I.K.); (H.Z.); (H.V.); (D.M.); (B.V.); (T.K.); (D.D.); (M.S.); (A.D.); (T.K.); (I.B.); (M.T.); (A.T.); (L.P.); (S.S.); (M.S.); (A.S.); (A.K.); (A.B.B.)
| | - Dominik Malekinusic
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (M.K.); (S.G.); (I.K.); (H.Z.); (H.V.); (D.M.); (B.V.); (T.K.); (D.D.); (M.S.); (A.D.); (T.K.); (I.B.); (M.T.); (A.T.); (L.P.); (S.S.); (M.S.); (A.S.); (A.K.); (A.B.B.)
| | - Borna Vrdoljak
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (M.K.); (S.G.); (I.K.); (H.Z.); (H.V.); (D.M.); (B.V.); (T.K.); (D.D.); (M.S.); (A.D.); (T.K.); (I.B.); (M.T.); (A.T.); (L.P.); (S.S.); (M.S.); (A.S.); (A.K.); (A.B.B.)
| | - Tamara Knezevic
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (M.K.); (S.G.); (I.K.); (H.Z.); (H.V.); (D.M.); (B.V.); (T.K.); (D.D.); (M.S.); (A.D.); (T.K.); (I.B.); (M.T.); (A.T.); (L.P.); (S.S.); (M.S.); (A.S.); (A.K.); (A.B.B.)
| | - Katarina Horvat Pavlov
- Department of Pathology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (K.H.P.); (E.L.); (M.M.); (S.S.); (S.S.)
| | - Domagoj Drmic
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (M.K.); (S.G.); (I.K.); (H.Z.); (H.V.); (D.M.); (B.V.); (T.K.); (D.D.); (M.S.); (A.D.); (T.K.); (I.B.); (M.T.); (A.T.); (L.P.); (S.S.); (M.S.); (A.S.); (A.K.); (A.B.B.)
| | - Miro Staroveski
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (M.K.); (S.G.); (I.K.); (H.Z.); (H.V.); (D.M.); (B.V.); (T.K.); (D.D.); (M.S.); (A.D.); (T.K.); (I.B.); (M.T.); (A.T.); (L.P.); (S.S.); (M.S.); (A.S.); (A.K.); (A.B.B.)
| | - Antonija Djuzel
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (M.K.); (S.G.); (I.K.); (H.Z.); (H.V.); (D.M.); (B.V.); (T.K.); (D.D.); (M.S.); (A.D.); (T.K.); (I.B.); (M.T.); (A.T.); (L.P.); (S.S.); (M.S.); (A.S.); (A.K.); (A.B.B.)
| | - Zoran Rajkovic
- Department of Surgery, Faculty of Dental Medicine and Health, University of Osijek, 31000 Osijek, Croatia;
| | - Toni Kolak
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (M.K.); (S.G.); (I.K.); (H.Z.); (H.V.); (D.M.); (B.V.); (T.K.); (D.D.); (M.S.); (A.D.); (T.K.); (I.B.); (M.T.); (A.T.); (L.P.); (S.S.); (M.S.); (A.S.); (A.K.); (A.B.B.)
| | - Eva Lovric
- Department of Pathology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (K.H.P.); (E.L.); (M.M.); (S.S.); (S.S.)
| | - Marija Milavic
- Department of Pathology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (K.H.P.); (E.L.); (M.M.); (S.S.); (S.S.)
| | - Suncana Sikiric
- Department of Pathology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (K.H.P.); (E.L.); (M.M.); (S.S.); (S.S.)
| | - Ivan Barisic
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (M.K.); (S.G.); (I.K.); (H.Z.); (H.V.); (D.M.); (B.V.); (T.K.); (D.D.); (M.S.); (A.D.); (T.K.); (I.B.); (M.T.); (A.T.); (L.P.); (S.S.); (M.S.); (A.S.); (A.K.); (A.B.B.)
| | - Marijan Tepes
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (M.K.); (S.G.); (I.K.); (H.Z.); (H.V.); (D.M.); (B.V.); (T.K.); (D.D.); (M.S.); (A.D.); (T.K.); (I.B.); (M.T.); (A.T.); (L.P.); (S.S.); (M.S.); (A.S.); (A.K.); (A.B.B.)
| | - Ante Tvrdeic
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (M.K.); (S.G.); (I.K.); (H.Z.); (H.V.); (D.M.); (B.V.); (T.K.); (D.D.); (M.S.); (A.D.); (T.K.); (I.B.); (M.T.); (A.T.); (L.P.); (S.S.); (M.S.); (A.S.); (A.K.); (A.B.B.)
| | - Leonardo Patrlj
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (M.K.); (S.G.); (I.K.); (H.Z.); (H.V.); (D.M.); (B.V.); (T.K.); (D.D.); (M.S.); (A.D.); (T.K.); (I.B.); (M.T.); (A.T.); (L.P.); (S.S.); (M.S.); (A.S.); (A.K.); (A.B.B.)
| | - Sanja Strbe
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (M.K.); (S.G.); (I.K.); (H.Z.); (H.V.); (D.M.); (B.V.); (T.K.); (D.D.); (M.S.); (A.D.); (T.K.); (I.B.); (M.T.); (A.T.); (L.P.); (S.S.); (M.S.); (A.S.); (A.K.); (A.B.B.)
| | - Marija Sola
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (M.K.); (S.G.); (I.K.); (H.Z.); (H.V.); (D.M.); (B.V.); (T.K.); (D.D.); (M.S.); (A.D.); (T.K.); (I.B.); (M.T.); (A.T.); (L.P.); (S.S.); (M.S.); (A.S.); (A.K.); (A.B.B.)
| | - Andrej Situm
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (M.K.); (S.G.); (I.K.); (H.Z.); (H.V.); (D.M.); (B.V.); (T.K.); (D.D.); (M.S.); (A.D.); (T.K.); (I.B.); (M.T.); (A.T.); (L.P.); (S.S.); (M.S.); (A.S.); (A.K.); (A.B.B.)
| | - Antonio Kokot
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (M.K.); (S.G.); (I.K.); (H.Z.); (H.V.); (D.M.); (B.V.); (T.K.); (D.D.); (M.S.); (A.D.); (T.K.); (I.B.); (M.T.); (A.T.); (L.P.); (S.S.); (M.S.); (A.S.); (A.K.); (A.B.B.)
| | - Alenka Boban Blagaic
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (M.K.); (S.G.); (I.K.); (H.Z.); (H.V.); (D.M.); (B.V.); (T.K.); (D.D.); (M.S.); (A.D.); (T.K.); (I.B.); (M.T.); (A.T.); (L.P.); (S.S.); (M.S.); (A.S.); (A.K.); (A.B.B.)
| | - Anita Skrtic
- Department of Pathology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (K.H.P.); (E.L.); (M.M.); (S.S.); (S.S.)
| | - Sven Seiwerth
- Department of Pathology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (K.H.P.); (E.L.); (M.M.); (S.S.); (S.S.)
| | - Predrag Sikiric
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (M.K.); (S.G.); (I.K.); (H.Z.); (H.V.); (D.M.); (B.V.); (T.K.); (D.D.); (M.S.); (A.D.); (T.K.); (I.B.); (M.T.); (A.T.); (L.P.); (S.S.); (M.S.); (A.S.); (A.K.); (A.B.B.)
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Knezevic M, Gojkovic S, Krezic I, Zizek H, Malekinusic D, Vrdoljak B, Knezevic T, Vranes H, Drmic D, Staroveski M, Djuzel A, Rajkovic Z, Kolak T, Lovric E, Milavic M, Sikiric S, Tvrdeic A, Patrlj L, Strbe S, Sola M, Situm A, Kokot A, Boban Blagaic A, Skrtic A, Seiwerth S, Sikiric P. Occluded Superior Mesenteric Artery and Vein. Therapy with the Stable Gastric Pentadecapeptide BPC 157. Biomedicines 2021; 9:biomedicines9070792. [PMID: 34356860 PMCID: PMC8301404 DOI: 10.3390/biomedicines9070792] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2021] [Revised: 06/24/2021] [Accepted: 07/02/2021] [Indexed: 12/13/2022] Open
Abstract
Background. We investigated the occluded essential vessel tributaries, both arterial and venous, occluded superior mesenteric vein and artery in rats, consequent noxious syndrome, peripherally and centrally. As therapy, we hypothesized the rapidly activated alternative bypassing pathways, arterial and venous, and the stable gastric pentadecapeptide BPC 157 since it rapidly alleviated venous occlusion syndromes. Methods. Assessments were performed for 30 min (gross recording, venography, ECG, pressure, microscopy, biochemistry, and oxidative stress), including portal hypertension, caval hypertension, aortal hypotension, and centrally, the superior sagittal sinus hypertension; systemic arterial and venous thrombosis, ECG disturbances, MDA-tissue increase, the multiple organs lesions, heart, lung, liver, kidney and gastrointestinal tract, including brain (swelling, and cortex (cerebral, cerebellar), hypothalamus/thalamus, hippocampus lesions). Rats received BPC 157 medication (10 µg/kg, 10 ng/kg) intraperitoneally at 1 min ligation-time. Results. BPC 157 rapidly activated collateral pathways. These collateral loops were the superior mesenteric vein-inferior anterior pancreaticoduodenal vein-superior anterior pancreaticoduodenal vein-pyloric vein-portal vein pathway, an alternative pathway toward inferior caval vein via the united middle colic vein and inferior mesenteric vein through the left colic vein, and the inferior anterior pancreaticoduodenal artery and inferior mesenteric artery. Consequently, BPC 157 counteracted the superior sagittal sinus, portal and caval hypertension, aortal hypotension, progressing venous and arterial thrombosis peripherally and centrally, ECG disturbances attenuated. Markedly, the multiple organs lesions, heart, lung, liver, kidney, and gastrointestinal tract, in particular, as well as brain lesions, and oxidative stress in tissues were attenuated. Conclusions. BPC 157 therapy rapidly recovered rats, which have complete occlusion of the superior mesenteric vein and artery.
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Affiliation(s)
- Mario Knezevic
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (M.K.); (S.G.); (I.K.); (H.Z.); (D.M.); (B.V.); (T.K.); (H.V.); (D.D.); (M.S.); (A.D.); (T.K.); (A.T.); (L.P.); (S.S.); (M.S.); (A.S.); (A.B.B.)
| | - Slaven Gojkovic
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (M.K.); (S.G.); (I.K.); (H.Z.); (D.M.); (B.V.); (T.K.); (H.V.); (D.D.); (M.S.); (A.D.); (T.K.); (A.T.); (L.P.); (S.S.); (M.S.); (A.S.); (A.B.B.)
| | - Ivan Krezic
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (M.K.); (S.G.); (I.K.); (H.Z.); (D.M.); (B.V.); (T.K.); (H.V.); (D.D.); (M.S.); (A.D.); (T.K.); (A.T.); (L.P.); (S.S.); (M.S.); (A.S.); (A.B.B.)
| | - Helena Zizek
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (M.K.); (S.G.); (I.K.); (H.Z.); (D.M.); (B.V.); (T.K.); (H.V.); (D.D.); (M.S.); (A.D.); (T.K.); (A.T.); (L.P.); (S.S.); (M.S.); (A.S.); (A.B.B.)
| | - Dominik Malekinusic
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (M.K.); (S.G.); (I.K.); (H.Z.); (D.M.); (B.V.); (T.K.); (H.V.); (D.D.); (M.S.); (A.D.); (T.K.); (A.T.); (L.P.); (S.S.); (M.S.); (A.S.); (A.B.B.)
| | - Borna Vrdoljak
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (M.K.); (S.G.); (I.K.); (H.Z.); (D.M.); (B.V.); (T.K.); (H.V.); (D.D.); (M.S.); (A.D.); (T.K.); (A.T.); (L.P.); (S.S.); (M.S.); (A.S.); (A.B.B.)
| | - Tamara Knezevic
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (M.K.); (S.G.); (I.K.); (H.Z.); (D.M.); (B.V.); (T.K.); (H.V.); (D.D.); (M.S.); (A.D.); (T.K.); (A.T.); (L.P.); (S.S.); (M.S.); (A.S.); (A.B.B.)
| | - Hrvoje Vranes
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (M.K.); (S.G.); (I.K.); (H.Z.); (D.M.); (B.V.); (T.K.); (H.V.); (D.D.); (M.S.); (A.D.); (T.K.); (A.T.); (L.P.); (S.S.); (M.S.); (A.S.); (A.B.B.)
| | - Domagoj Drmic
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (M.K.); (S.G.); (I.K.); (H.Z.); (D.M.); (B.V.); (T.K.); (H.V.); (D.D.); (M.S.); (A.D.); (T.K.); (A.T.); (L.P.); (S.S.); (M.S.); (A.S.); (A.B.B.)
| | - Miro Staroveski
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (M.K.); (S.G.); (I.K.); (H.Z.); (D.M.); (B.V.); (T.K.); (H.V.); (D.D.); (M.S.); (A.D.); (T.K.); (A.T.); (L.P.); (S.S.); (M.S.); (A.S.); (A.B.B.)
| | - Antonija Djuzel
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (M.K.); (S.G.); (I.K.); (H.Z.); (D.M.); (B.V.); (T.K.); (H.V.); (D.D.); (M.S.); (A.D.); (T.K.); (A.T.); (L.P.); (S.S.); (M.S.); (A.S.); (A.B.B.)
| | - Zoran Rajkovic
- Department of Surgery, Faculty of Dental Medicine and Health, University of Osijek, 31000 Osijek, Croatia;
| | - Toni Kolak
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (M.K.); (S.G.); (I.K.); (H.Z.); (D.M.); (B.V.); (T.K.); (H.V.); (D.D.); (M.S.); (A.D.); (T.K.); (A.T.); (L.P.); (S.S.); (M.S.); (A.S.); (A.B.B.)
| | - Eva Lovric
- Department of Pathology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (E.L.); (M.M.); (S.S.); (S.S.)
| | - Marija Milavic
- Department of Pathology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (E.L.); (M.M.); (S.S.); (S.S.)
| | - Suncana Sikiric
- Department of Pathology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (E.L.); (M.M.); (S.S.); (S.S.)
| | - Ante Tvrdeic
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (M.K.); (S.G.); (I.K.); (H.Z.); (D.M.); (B.V.); (T.K.); (H.V.); (D.D.); (M.S.); (A.D.); (T.K.); (A.T.); (L.P.); (S.S.); (M.S.); (A.S.); (A.B.B.)
| | - Leonardo Patrlj
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (M.K.); (S.G.); (I.K.); (H.Z.); (D.M.); (B.V.); (T.K.); (H.V.); (D.D.); (M.S.); (A.D.); (T.K.); (A.T.); (L.P.); (S.S.); (M.S.); (A.S.); (A.B.B.)
| | - Sanja Strbe
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (M.K.); (S.G.); (I.K.); (H.Z.); (D.M.); (B.V.); (T.K.); (H.V.); (D.D.); (M.S.); (A.D.); (T.K.); (A.T.); (L.P.); (S.S.); (M.S.); (A.S.); (A.B.B.)
| | - Marija Sola
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (M.K.); (S.G.); (I.K.); (H.Z.); (D.M.); (B.V.); (T.K.); (H.V.); (D.D.); (M.S.); (A.D.); (T.K.); (A.T.); (L.P.); (S.S.); (M.S.); (A.S.); (A.B.B.)
| | - Andrej Situm
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (M.K.); (S.G.); (I.K.); (H.Z.); (D.M.); (B.V.); (T.K.); (H.V.); (D.D.); (M.S.); (A.D.); (T.K.); (A.T.); (L.P.); (S.S.); (M.S.); (A.S.); (A.B.B.)
| | - Antonio Kokot
- Department of Anatomy and Neuroscience, Faculty of Medicine Osijek, J. J. Strossmayer University of Osijek, 31000 Osijek, Croatia;
| | - Alenka Boban Blagaic
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (M.K.); (S.G.); (I.K.); (H.Z.); (D.M.); (B.V.); (T.K.); (H.V.); (D.D.); (M.S.); (A.D.); (T.K.); (A.T.); (L.P.); (S.S.); (M.S.); (A.S.); (A.B.B.)
| | - Anita Skrtic
- Department of Pathology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (E.L.); (M.M.); (S.S.); (S.S.)
- Correspondence: (A.S.); (P.S.); Tel.: +385-1-4566-980 (A.S.); +385-1-4566-833 (P.S.); Fax: +385-1-492-0050 (A.S. & P.S.)
| | - Sven Seiwerth
- Department of Pathology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (E.L.); (M.M.); (S.S.); (S.S.)
| | - Predrag Sikiric
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (M.K.); (S.G.); (I.K.); (H.Z.); (D.M.); (B.V.); (T.K.); (H.V.); (D.D.); (M.S.); (A.D.); (T.K.); (A.T.); (L.P.); (S.S.); (M.S.); (A.S.); (A.B.B.)
- Correspondence: (A.S.); (P.S.); Tel.: +385-1-4566-980 (A.S.); +385-1-4566-833 (P.S.); Fax: +385-1-492-0050 (A.S. & P.S.)
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Knezevic M, Gojkovic S, Krezic I, Zizek H, Malekinusic D, Vrdoljak B, Vranes H, Knezevic T, Barisic I, Horvat Pavlov K, Drmic D, Staroveski M, Djuzel A, Rajkovic Z, Kolak T, Kocman I, Lovric E, Milavic M, Sikiric S, Tvrdeic A, Patrlj L, Strbe S, Kokot A, Boban Blagaic A, Skrtic A, Seiwerth S, Sikiric P. Occlusion of the Superior Mesenteric Artery in Rats Reversed by Collateral Pathways Activation: Gastric Pentadecapeptide BPC 157 Therapy Counteracts Multiple Organ Dysfunction Syndrome; Intracranial, Portal, and Caval Hypertension; and Aortal Hypotension. Biomedicines 2021; 9:biomedicines9060609. [PMID: 34073625 PMCID: PMC8229949 DOI: 10.3390/biomedicines9060609] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2021] [Revised: 05/17/2021] [Accepted: 05/18/2021] [Indexed: 12/13/2022] Open
Abstract
Gastric pentadecapeptide BPC 157 therapy counteracts multiple organ dysfunction syndrome in rats, which have permanent occlusion of the superior mesenteric artery close to the abdominal aorta. Previously, when confronted with major vessel occlusion, its effect would rapidly activate collateral vessel pathways and resolve major venous occlusion syndromes (Pringle maneuver ischemia, reperfusion, Budd-Chiari syndrome) in rats. This would overwhelm superior mesenteric artery permanent occlusion, and result in local, peripheral, and central disturbances. Methods: Assessments, for 30 min (gross recording, angiography, ECG, pressure, microscopy, biochemistry, and oxidative stress), included the portal hypertension, caval hypertension, and aortal hypotension, and centrally, the superior sagittal sinus hypertension; systemic arterial and venous thrombosis; ECG disturbances; MDA-tissue increase; and multiple organ lesions and disturbances, including the heart, lung, liver, kidney, and gastrointestinal tract, in particular, as well as brain (cortex (cerebral, cerebellar), hypothalamus/thalamus, hippocampus). BPC 157 therapy (/kg, abdominal bath) (10 µg, 10 ng) was given for a 1-min ligation time. Results: BPC 157 rapidly recruits collateral vessels (inferior anterior pancreaticoduodenal artery and inferior mesenteric artery) that circumvent occlusion and ascertains blood flow distant from the occlusion in the superior mesenteric artery. Portal and caval hypertension, aortal hypotension, and, centrally, superior sagittal sinus hypertension were attenuated or eliminated, and ECG disturbances markedly mitigated. BPC 157 therapy almost annihilated venous and arterial thrombosis. Multiple organ lesions and disturbances (i.e., heart, lung, liver, and gastrointestinal tract, in particular, as well as brain) were largely attenuated. Conclusions: Rats with superior mesenteric artery occlusion may additionally undergo BPC 157 therapy as full counteraction of vascular occlusion-induced multiple organ dysfunction syndrome.
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Affiliation(s)
- Mario Knezevic
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (M.K.); (S.G.); (I.K.); (H.Z.); (D.M.); (B.V.); (H.V.); (T.K.); (I.B.); (D.D.); (M.S.); (A.D.); (T.K.); (I.K.); (A.T.); (L.P.); (S.S.); (A.B.B.)
| | - Slaven Gojkovic
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (M.K.); (S.G.); (I.K.); (H.Z.); (D.M.); (B.V.); (H.V.); (T.K.); (I.B.); (D.D.); (M.S.); (A.D.); (T.K.); (I.K.); (A.T.); (L.P.); (S.S.); (A.B.B.)
| | - Ivan Krezic
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (M.K.); (S.G.); (I.K.); (H.Z.); (D.M.); (B.V.); (H.V.); (T.K.); (I.B.); (D.D.); (M.S.); (A.D.); (T.K.); (I.K.); (A.T.); (L.P.); (S.S.); (A.B.B.)
| | - Helena Zizek
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (M.K.); (S.G.); (I.K.); (H.Z.); (D.M.); (B.V.); (H.V.); (T.K.); (I.B.); (D.D.); (M.S.); (A.D.); (T.K.); (I.K.); (A.T.); (L.P.); (S.S.); (A.B.B.)
| | - Dominik Malekinusic
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (M.K.); (S.G.); (I.K.); (H.Z.); (D.M.); (B.V.); (H.V.); (T.K.); (I.B.); (D.D.); (M.S.); (A.D.); (T.K.); (I.K.); (A.T.); (L.P.); (S.S.); (A.B.B.)
| | - Borna Vrdoljak
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (M.K.); (S.G.); (I.K.); (H.Z.); (D.M.); (B.V.); (H.V.); (T.K.); (I.B.); (D.D.); (M.S.); (A.D.); (T.K.); (I.K.); (A.T.); (L.P.); (S.S.); (A.B.B.)
| | - Hrvoje Vranes
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (M.K.); (S.G.); (I.K.); (H.Z.); (D.M.); (B.V.); (H.V.); (T.K.); (I.B.); (D.D.); (M.S.); (A.D.); (T.K.); (I.K.); (A.T.); (L.P.); (S.S.); (A.B.B.)
| | - Tamara Knezevic
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (M.K.); (S.G.); (I.K.); (H.Z.); (D.M.); (B.V.); (H.V.); (T.K.); (I.B.); (D.D.); (M.S.); (A.D.); (T.K.); (I.K.); (A.T.); (L.P.); (S.S.); (A.B.B.)
| | - Ivan Barisic
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (M.K.); (S.G.); (I.K.); (H.Z.); (D.M.); (B.V.); (H.V.); (T.K.); (I.B.); (D.D.); (M.S.); (A.D.); (T.K.); (I.K.); (A.T.); (L.P.); (S.S.); (A.B.B.)
| | - Katarina Horvat Pavlov
- Department of Pathology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (K.H.P.); (E.L.); (M.M.); (S.S.); (A.S.); (S.S.)
| | - Domagoj Drmic
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (M.K.); (S.G.); (I.K.); (H.Z.); (D.M.); (B.V.); (H.V.); (T.K.); (I.B.); (D.D.); (M.S.); (A.D.); (T.K.); (I.K.); (A.T.); (L.P.); (S.S.); (A.B.B.)
| | - Miro Staroveski
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (M.K.); (S.G.); (I.K.); (H.Z.); (D.M.); (B.V.); (H.V.); (T.K.); (I.B.); (D.D.); (M.S.); (A.D.); (T.K.); (I.K.); (A.T.); (L.P.); (S.S.); (A.B.B.)
| | - Antonija Djuzel
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (M.K.); (S.G.); (I.K.); (H.Z.); (D.M.); (B.V.); (H.V.); (T.K.); (I.B.); (D.D.); (M.S.); (A.D.); (T.K.); (I.K.); (A.T.); (L.P.); (S.S.); (A.B.B.)
| | - Zoran Rajkovic
- Department of Surgery, Faculty of Dental Medicine and Health, University of Osijek, 31000 Osijek, Croatia;
| | - Toni Kolak
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (M.K.); (S.G.); (I.K.); (H.Z.); (D.M.); (B.V.); (H.V.); (T.K.); (I.B.); (D.D.); (M.S.); (A.D.); (T.K.); (I.K.); (A.T.); (L.P.); (S.S.); (A.B.B.)
| | - Ivica Kocman
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (M.K.); (S.G.); (I.K.); (H.Z.); (D.M.); (B.V.); (H.V.); (T.K.); (I.B.); (D.D.); (M.S.); (A.D.); (T.K.); (I.K.); (A.T.); (L.P.); (S.S.); (A.B.B.)
| | - Eva Lovric
- Department of Pathology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (K.H.P.); (E.L.); (M.M.); (S.S.); (A.S.); (S.S.)
| | - Marija Milavic
- Department of Pathology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (K.H.P.); (E.L.); (M.M.); (S.S.); (A.S.); (S.S.)
| | - Suncana Sikiric
- Department of Pathology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (K.H.P.); (E.L.); (M.M.); (S.S.); (A.S.); (S.S.)
| | - Ante Tvrdeic
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (M.K.); (S.G.); (I.K.); (H.Z.); (D.M.); (B.V.); (H.V.); (T.K.); (I.B.); (D.D.); (M.S.); (A.D.); (T.K.); (I.K.); (A.T.); (L.P.); (S.S.); (A.B.B.)
| | - Leonardo Patrlj
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (M.K.); (S.G.); (I.K.); (H.Z.); (D.M.); (B.V.); (H.V.); (T.K.); (I.B.); (D.D.); (M.S.); (A.D.); (T.K.); (I.K.); (A.T.); (L.P.); (S.S.); (A.B.B.)
| | - Sanja Strbe
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (M.K.); (S.G.); (I.K.); (H.Z.); (D.M.); (B.V.); (H.V.); (T.K.); (I.B.); (D.D.); (M.S.); (A.D.); (T.K.); (I.K.); (A.T.); (L.P.); (S.S.); (A.B.B.)
| | - Antonio Kokot
- Department of Anatomy and Neuroscience, School of Medicine, Josip Juraj Strossmayer University of Osijek, 31000 Osijek, Croatia;
| | - Alenka Boban Blagaic
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (M.K.); (S.G.); (I.K.); (H.Z.); (D.M.); (B.V.); (H.V.); (T.K.); (I.B.); (D.D.); (M.S.); (A.D.); (T.K.); (I.K.); (A.T.); (L.P.); (S.S.); (A.B.B.)
| | - Anita Skrtic
- Department of Pathology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (K.H.P.); (E.L.); (M.M.); (S.S.); (A.S.); (S.S.)
| | - Sven Seiwerth
- Department of Pathology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (K.H.P.); (E.L.); (M.M.); (S.S.); (A.S.); (S.S.)
| | - Predrag Sikiric
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (M.K.); (S.G.); (I.K.); (H.Z.); (D.M.); (B.V.); (H.V.); (T.K.); (I.B.); (D.D.); (M.S.); (A.D.); (T.K.); (I.K.); (A.T.); (L.P.); (S.S.); (A.B.B.)
- Correspondence: ; Tel.: +385-1-4566-833; Fax: +385-1-492-0050
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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.
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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
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Xu C, Sun L, Ren F, Huang P, Tian Z, Cui J, Zhang W, Wang S, Zhang K, He L, Zhang W, Zhang C, Hao Q, Zhang Y, Li M, Li W. Preclinical safety evaluation of body protective compound-157, a potential drug for treating various wounds. Regul Toxicol Pharmacol 2020; 114:104665. [PMID: 32334036 DOI: 10.1016/j.yrtph.2020.104665] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2019] [Revised: 03/09/2020] [Accepted: 04/17/2020] [Indexed: 12/22/2022]
Abstract
BPC157 displays protective activity in various organs and tissues. This report presents preclinical toxicity studies with BPC157 in mice, rats, rabbits and dogs. The single-dose toxicity study did not show any test-related effects that could be attributed to the test article. In repeated-dose toxicity evaluations, BPC157 was well tolerated in dogs, with no abnormal changes between the BPC157-treated groups and the solvent control group, with the exception of a decrease in creatinine level at a dose of 2 mg/kg but not at lower doses. The animals recovered spontaneously after 2 weeks of withdrawal. This may be due to the pharmacological activity of BPC157. A local tolerance test showed that the irritation caused by BPC157 was mild. BPC157 also showed no genetic or embryo-fetal toxicity. In summary, BPC157 was well tolerated and did not cause any serious toxicity in mice, rats, rabbits and dogs. These preclinical safety data contribute to the initiation of an ongoing clinical study. Based on the stability and protective effect of BPC157, which has been widely reported, BPC157 may have a better application prospect than the widely used cytokine drugs in wound therapy.
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Affiliation(s)
- Chuanyang Xu
- State Key Laboratory of Cancer Biology, Biotechnology Center, School of Pharmacy, Fourth Military Medical University, Xi'an, 710032, China
| | - Lijuan Sun
- Department of Ophthalmology, Eye Institute of Chinese PLA, Xijing Hospital, Fourth Military Medical University, Xi'an, 710032, China
| | - FengLing Ren
- School of Public Health, Health Science Center, Xi'an Jiaotong University, Xi'an, 710061, China
| | - Ping Huang
- The Brigade of Undergraduates, The Fourth Military Medical University, Xi'an, 710032, China
| | - Zhuang Tian
- The Brigade of Undergraduates, The Fourth Military Medical University, Xi'an, 710032, China
| | - Jiazhen Cui
- The Brigade of Undergraduates, The Fourth Military Medical University, Xi'an, 710032, China
| | - Wangqian Zhang
- State Key Laboratory of Cancer Biology, Biotechnology Center, School of Pharmacy, Fourth Military Medical University, Xi'an, 710032, China
| | - Shuning Wang
- State Key Laboratory of Cancer Biology, Biotechnology Center, School of Pharmacy, Fourth Military Medical University, Xi'an, 710032, China
| | - Kuo Zhang
- State Key Laboratory of Cancer Biology, Biotechnology Center, School of Pharmacy, Fourth Military Medical University, Xi'an, 710032, China
| | - Lei He
- State Key Laboratory of Cancer Biology, Biotechnology Center, School of Pharmacy, Fourth Military Medical University, Xi'an, 710032, China
| | - Wei Zhang
- State Key Laboratory of Cancer Biology, Biotechnology Center, School of Pharmacy, Fourth Military Medical University, Xi'an, 710032, China
| | - Cun Zhang
- State Key Laboratory of Cancer Biology, Biotechnology Center, School of Pharmacy, Fourth Military Medical University, Xi'an, 710032, China
| | - Qiang Hao
- State Key Laboratory of Cancer Biology, Biotechnology Center, School of Pharmacy, Fourth Military Medical University, Xi'an, 710032, China
| | - Yingqi Zhang
- State Key Laboratory of Cancer Biology, Biotechnology Center, School of Pharmacy, Fourth Military Medical University, Xi'an, 710032, China
| | - Meng Li
- State Key Laboratory of Cancer Biology, Biotechnology Center, School of Pharmacy, Fourth Military Medical University, Xi'an, 710032, China.
| | - Weina Li
- State Key Laboratory of Cancer Biology, Biotechnology Center, School of Pharmacy, Fourth Military Medical University, Xi'an, 710032, China.
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Sikiric P, Hahm KB, Blagaic AB, Tvrdeic A, Pavlov KH, Petrovic A, Kokot A, Gojkovic S, Krezic I, Drmic D, Rucman, R, Seiwerth S. Stable Gastric Pentadecapeptide BPC 157, Robert's Stomach Cytoprotection/Adaptive Cytoprotection/Organoprotection, and Selye's Stress Coping Response: Progress, Achievements, and the Future. Gut Liver 2020; 14:153-167. [PMID: 31158953 PMCID: PMC7096228 DOI: 10.5009/gnl18490] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/05/2018] [Revised: 01/10/2019] [Accepted: 01/21/2019] [Indexed: 12/14/2022] Open
Abstract
We reviewed again the significance of the stable gastric pentadecapeptide BPC 157 as a likely mediator of Robert's stomach cytoprotection/adaptive cytoprotection and organoprotection and as novel mediator of Selye's stress coping response to reestablish homeostasis. Specific points of BPC 157 therapy and the original concept of Robert's cytoprotection/adaptive cytoprotection/organoprotection are discussed, including the beneficial effects of BPC 157. First, BPC 157 protects stomach cells and maintains gastric integrity against various noxious agents (Robert's killing cell by contact) and is continuously present in the gastric mucosa and gastric juice. Additionally, BPC 157 protects against the adverse effects of alcohol and nonsteroidal anti-inflammatory drugs on the gastric epithelium and other epithelia, that is, skin, liver, pancreas, heart (organoprotection), and brain, thereby suggesting its use in wound healing. Additionally, BPC 157 counteracts gastric endothelial injury that precedes and induces damage to the gastric epithelium and generalizes "gastric endothelial protection" to protection of the endothelium of other vessels (thrombosis, prolonged bleeding, and thrombocytopenia). BPC 157 also has an effect on blood vessels, resulting in vessel recruitment that circumvents vessel occlusion and the development of additional shunting and rapid bypass loops to rapidly reestablish the integrity of blood flow (ischemic/reperfusion colitis, duodenal lesions, cecal perforation, and inferior vena caval occlusion). Lastly, BPC 157 counteracts tumor cachexia, muscle wasting, and increases in pro-inflammatory/procachectic cytokines, such as interleukin-6 and tumor necrosis factor-α, and significantly corrects deranged muscle proliferation and myogenesis through changes in the expression of FoxO3a, p-AKT, p-mTOR, and p-GSK-3β (mitigating cancer cachexia).
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Affiliation(s)
- Predrag Sikiric
- Department of Pharmacology, Medical Faculty, University of Zagreb, Zagreb, Croatia
| | - Ki-Baik Hahm
- Digestive Disease Center, CHA Bundang Medical Center, CHA University School of Medicine, Seongnam, Korea
| | - Alenka Boban Blagaic
- Department of Pharmacology, Medical Faculty, University of Zagreb, Zagreb, Croatia
| | - Ante Tvrdeic
- Department of Pharmacology, Medical Faculty, University of Zagreb, Zagreb, Croatia
| | | | - Andrea Petrovic
- Department of Pathology, Medical Faculty, University of Zagreb, Zagreb, Croatia
| | - Antonio Kokot
- Department of Pharmacology, Medical Faculty, University of Zagreb, Zagreb, Croatia
| | - Slaven Gojkovic
- Department of Pharmacology, Medical Faculty, University of Zagreb, Zagreb, Croatia
| | - Ivan Krezic
- Department of Pharmacology, Medical Faculty, University of Zagreb, Zagreb, Croatia
| | - Domagoj Drmic
- Department of Pharmacology, Medical Faculty, University of Zagreb, Zagreb, Croatia
| | - Rudolf Rucman,
- Department of Pharmacology, Medical Faculty, University of Zagreb, Zagreb, Croatia
| | - Sven Seiwerth
- Department of Pathology, Medical Faculty, University of Zagreb, Zagreb, Croatia
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18
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Gojkovic S, Krezic I, Vrdoljak B, Malekinusic D, Barisic I, Petrovic A, Horvat Pavlov K, Kolovrat M, Duzel A, Knezevic M, Kasnik Kovac K, Drmic D, Batelja Vuletic L, Kokot A, Boban Blagaic A, Seiwerth S, Sikiric P. Pentadecapeptide BPC 157 resolves suprahepatic occlusion of the inferior caval vein, Budd-Chiari syndrome model in rats. World J Gastrointest Pathophysiol 2020; 11:1-19. [PMID: 32226643 PMCID: PMC7093306 DOI: 10.4291/wjgp.v11.i1.1] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/07/2019] [Revised: 12/20/2019] [Accepted: 02/11/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Recently, as a possible therapy resolving solution, pentadecapeptide BPC 157 therapy, has been used in alleviating various vascular occlusion disturbances. BPC 157 was previously reviewed as novel mediator of Robert cytoprotection and endothelium protection in the stomach, and gut-brain axis, beneficial therapy in gastrointestinal tract, with particular reference to vascular recruitment, ulcerative colitis and tumor cachexia, and other tissues healing. Here we raised new hypothesis about BPC 157 therapy in the Budd-Chiari syndrome in rats, rapid bypassing of the suprahepatic inferior caval vein occlusion, and rats recovery with the active and effective pharmacotherapy treatment.
AIM To investigate Budd-Chiari syndrome model (inferior caval vein suprahepatic occlusion) resolution, since BPC 157 resolves various rat vascular occlusion.
METHODS We assessed the activated bypassing pathways between the inferior and superior caval veins and portocaval shunt, counteracted caval/portal hypertension, aortal hypotension, venous/arterial thrombosis, electrocardiogram disturbances, liver and gastrointestinal lesions (i.e., stomach and duodenum hemorrhages, in particular, congestion). Rats with suprahepatic occlusion of the inferior vena cava by ligation were medicated at 1 min, 15 min, 24 h, or 48 h post-ligation. Medication consisted of 10 µg/kg BPC 157, 10 ng BPC 157 or 5 mL/kg saline, administered once as an abdominal bath or intragastric application. Gross and microscopic observations were made, in addition to assessments of electrical activity of the heart (electrocardiogram), portal and caval hypertension, aortal hypotension, thrombosis, hepatomegaly, splenomegaly and venography. Furthermore, levels of nitric oxide, malondialdehyde in the liver and serum enzymes were determined.
RESULTS BPC 157 counteracted increased P wave amplitude, tachycardia and ST-elevation, i.e., right heart failure from acute thrombotic coronary occlusion. The bypassing pathway of the inferior vena cava-azygos (hemiazygos) vein-superior vena cava and portocaval shunt occurred rapidly. Even with severe caval ˃ portal hypertension, BPC 157 antagonized portal and caval hypertension and aortal hypotension, and also reduced refractory ascites. Thrombosis of portal vein tributaries, inferior vena cava, and hepatic and coronary arteries was attenuated. In addition, there was reduced pathology of the lungs (severe capillary congestion) and liver (dilated central veins and terminal portal venules), decreased intestine hemorrhagic lesions (substantial capillary congestion, submucosal edema and architecture loss), and increased liver and spleen weight. During the period of ligation, nitric oxide- and malondialdehyde-levels in the liver remained within normal healthy values, and increases in serum enzymes were markedly reduced.
CONCLUSION BPC 157 counteracts Budd Chiari syndrome in rats.
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Affiliation(s)
- Slaven Gojkovic
- Departments of Pharmacology and Pathology, Medical Faculty University of Zagreb, Zagreb 10000, Croatia
| | - Ivan Krezic
- Departments of Pharmacology and Pathology, Medical Faculty University of Zagreb, Zagreb 10000, Croatia
| | - Borna Vrdoljak
- Departments of Pharmacology and Pathology, Medical Faculty University of Zagreb, Zagreb 10000, Croatia
| | - Dominik Malekinusic
- Departments of Pharmacology and Pathology, Medical Faculty University of Zagreb, Zagreb 10000, Croatia
| | - Ivan Barisic
- Departments of Pharmacology and Pathology, Medical Faculty University of Zagreb, Zagreb 10000, Croatia
| | - Andreja Petrovic
- Departments of Pharmacology and Pathology, Medical Faculty University of Zagreb, Zagreb 10000, Croatia
| | - Katarina Horvat Pavlov
- Departments of Pharmacology and Pathology, Medical Faculty University of Zagreb, Zagreb 10000, Croatia
| | - Marijan Kolovrat
- Departments of Pharmacology and Pathology, Medical Faculty University of Zagreb, Zagreb 10000, Croatia
| | - Antonija Duzel
- Departments of Pharmacology and Pathology, Medical Faculty University of Zagreb, Zagreb 10000, Croatia
| | - Mario Knezevic
- Departments of Pharmacology and Pathology, Medical Faculty University of Zagreb, Zagreb 10000, Croatia
| | - Katarina Kasnik Kovac
- Departments of Pharmacology and Pathology, Medical Faculty University of Zagreb, Zagreb 10000, Croatia
| | - Domagoj Drmic
- Departments of Pharmacology and Pathology, Medical Faculty University of Zagreb, Zagreb 10000, Croatia
| | - Lovorka Batelja Vuletic
- Departments of Pharmacology and Pathology, Medical Faculty University of Zagreb, Zagreb 10000, Croatia
| | - Antonio Kokot
- Departments of Pharmacology and Pathology, Medical Faculty University of Zagreb, Zagreb 10000, Croatia
| | - Alenka Boban Blagaic
- Departments of Pharmacology and Pathology, Medical Faculty University of Zagreb, Zagreb 10000, Croatia
| | - Sven Seiwerth
- Departments of Pharmacology and Pathology, Medical Faculty University of Zagreb, Zagreb 10000, Croatia
| | - Predrag Sikiric
- Departments of Pharmacology and Pathology, Medical Faculty University of Zagreb, Zagreb 10000, Croatia
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Cyclophosphamide induced stomach and duodenal lesions as a NO-system disturbance in rats: L-NAME, L-arginine, stable gastric pentadecapeptide BPC 157. Inflammopharmacology 2017; 25:255-264. [PMID: 28255738 DOI: 10.1007/s10787-017-0330-7] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2016] [Accepted: 02/15/2017] [Indexed: 12/13/2022]
Abstract
We revealed a new point with cyclophosphamide (150 mg/kg/day intraperitoneally for 7 days): we counteracted both rat stomach and duodenal ulcers and increased NO- and MDA-levels in these tissues. As a NO-system effect, BPC 157 therapy (10 µg/kg, 10 ng/kg, intraperitoneally once a day or in drinking water, till the sacrifice) attenuated the increased NO- and MDA-levels and nullified, in rats, severe cyclophosphamide-ulcers and even stronger stomach and duodenal lesions after cyclophosphamide + L-NAME (5 mg/kg intraperitoneally once a day). L-arginine (100 mg/kg intraperitoneally once a day not effective alone) led L-NAME-values only to the control values (cyclophosphamide + L-NAME + L-arginine-rats). Briefly, rats were sacrificed at 24 h after last administration on days 1, 2, 3, or 7, and assessment included sum of longest lesions diameters (mm) in the stomach and duodenum, oxidative stress by quantifying thiobarbituric acid reactivity as malondialdehyde equivalents (MDA), NO in stomach and duodenal tissue samples using the Griess reaction. All these parameters were highly exaggerated in rats who underwent cyclophosphamide treatment. We identified high MDA-tissue values, high NO-tissue values, ulcerogenic and beneficial potential in cyclophosphamide-L-NAME-L-arginine-BPC 157 relationships. This suggests that in cyclophosphamide damaged rats, NO excessive release generated by the inducible isozyme, damages the vascular wall and other tissue cells, especially in combination with reactive oxygen intermediates, while failing endothelial production and resulting in further aggravation by L-NAME which was inhibited by L-arginine. Finally, BPC 157, due to its special relations with NO-system, may both lessen increased MDA- and NO-tissues values and counteract effects of both cyclophosphamide and L-NAME on stomach and duodenal lesions.
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Sikiric P, Seiwerth S, Rucman R, Kolenc D, Vuletic LB, Drmic D, Grgic T, Strbe S, Zukanovic G, Crvenkovic D, Madzarac G, Rukavina I, Sucic M, Baric M, Starcevic N, Krstonijevic Z, Bencic ML, Filipcic I, Rokotov DS, Vlainic J. Brain-gut Axis and Pentadecapeptide BPC 157: Theoretical and Practical Implications. Curr Neuropharmacol 2017; 14:857-865. [PMID: 27138887 PMCID: PMC5333585 DOI: 10.2174/1570159x13666160502153022] [Citation(s) in RCA: 42] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2016] [Revised: 03/17/2016] [Accepted: 04/21/2016] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND Brain-gut interaction involves, among others, peptidergic growth factors which are native in GI tract and have strong antiulcer potency and thus could from periphery beneficially affect CNS-disorders. We focused on the stable gastric pentadecapeptide BPC 157, an antiulcer peptidergic agent, safe in inflammatory bowel disease trials and now in multiple sclerosis trial, native and stable in human gastric juice. METHODS Review of our research on BPC 157 in terms of brain-gut axis. RESULTS BPC 157 may serve as a novel mediator of Robert's cytoprotection, involved in maintaining of GI mucosa integrity, with no toxic effect. BPC 157 was successful in the therapy of GI tract, periodontitis, liver and pancreas lesions, and in the healing of various tissues and wounds. Stimulated Egr-1 gene, NAB2, FAK-paxillin and JAK-2 pathways are hitherto implicated. Initially corresponding beneficial central influence was seen when BPC 157 was given peripherally and a serotonin release in particular brain areas, mostly nigrostriatal, was changed. BPC 157 modulates serotonergic and dopaminergic systems, beneficially affects various behavioral disturbances that otherwise appeared due to specifically (over)stimulated/damaged neurotransmitters systems. Besides, BPC 157 has neuroprotective effects: protects somatosensory neurons; peripheral nerve regeneration appearent after transection; after traumatic brain injury counteracts the otherwise progressing course, in rat spinal cord compression with tail paralysis, axonal and neuronal necrosis, demyelination, cyst formation and rescues tail function in both short-terms and long-terms; after NSAIDs or insulin overdose or cuprizone encephalopathies were attenuated along with GI, liver and vascular injuries. CONCLUSION BPC 157, a gastric peptide, may serve as remedy in various CNS-disorders.
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Affiliation(s)
- Predrag Sikiric
- Medical Faculty, University of Zagreb, Šalata 3, 10000 Zagreb, Croatia
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Hsieh MJ, Liu HT, Wang CN, Huang HY, Lin Y, Ko YS, Wang JS, Chang VHS, Pang JHS. Therapeutic potential of pro-angiogenic BPC157 is associated with VEGFR2 activation and up-regulation. J Mol Med (Berl) 2016; 95:323-333. [PMID: 27847966 DOI: 10.1007/s00109-016-1488-y] [Citation(s) in RCA: 45] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2016] [Revised: 09/20/2016] [Accepted: 11/07/2016] [Indexed: 02/06/2023]
Abstract
BPC 157, a pentadecapeptide with extensive healing effects, has recently been suggested to contribute to angiogenesis. However, the underlying mechanism is not yet clear. The present study aimed to explore the potential therapeutic effect and pro-angiogenic mechanism of BPC 157. As demonstrated by the chick chorioallantoic membrane (CAM) assay and endothelial tube formation assay, BPC 157 could increase the vessel density both in vivo and in vitro, respectively. BPC 157 could also accelerate the recovery of blood flow in the ischemic muscle of the rat hind limb as detected by laser Doppler scanning, indicating the promotion of angiogenesis. Histological analysis of the hind limb muscle confirmed the increased number of vessels and the enhanced vascular expression of vascular endothelial growth factor receptor 2 (VEGFR2) in rat with BPC 157 treatment. In vitro study using human vascular endothelial cells further confirmed the increased mRNA and protein expressions of VEGFR2 but not VEGF-A by BPC 157. In addition, BPC 157 could promote VEGFR2 internalization in vascular endothelial cells which was blocked in the presence of dynasore, an inhibitor of endocytosis. BPC 157 time dependently activated the VEGFR2-Akt-eNOS signaling pathway which could also be suppressed by dynasore. The increase of endothelial tube formation induced by BPC 157 was also inhibited by dynasore. This study demonstrates the pro-angiogenic effects of BPC 157 that is associated with the increased expression, internalization of VEGFR2, and the activation of VEGFR2-Akt-eNOS signaling pathway. BPC 157 promotes angiogenesis in CAM assay and tube formation assay. BPC 157 accelerates the blood flow recovery and vessel number in rats with hind limb ischemia. BPC 157 up-regulates VEGFR2 expression in rats with hind limb ischemia and endothelial cell culture. BPC 157 promotes VEGFR2 internalization in association with VEGFR2-Akt-eNOS activation. KEY MESSAGE BPC 157 promotes angiogenesis in CAM assay and tube formation assay. BPC 157 accelerates the blood flow recovery and vessel number in rats with hind limb ischemia. BPC 157 up-regulates VEGFR2 expression in rats with hind limb ischemia and endothelial cell culture. BPC 157 promotes VEGFR2 internalization in association with VEGFR2-Akt-eNOS activation.
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Affiliation(s)
- Ming-Jer Hsieh
- Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, 259 Wen-Hwa 1st Road, Kwei-Shan, Tao-Yuan City, Taiwan, Republic Of China.,Division of Cardiology, Department of Internal Medicine, Chang Gung Memorial Hospital-Lin-kou, Chang Gung University, Tao-Yuan City, Taiwan, Republic Of China
| | - Hsien-Ta Liu
- Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, 259 Wen-Hwa 1st Road, Kwei-Shan, Tao-Yuan City, Taiwan, Republic Of China.,Division of Family Medicine, Shuang Ho Hospital, Taipei Medical University, Taipei, Taiwan, Republic Of China.,School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
| | - Chao-Nin Wang
- Department of Obstetrics and Gynecology, Lin-Kou Medical Center, Chang Gung Memorial Hospital, Tao-Yuan City, Taiwan, Republic Of China
| | - Hsiu-Yun Huang
- Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, 259 Wen-Hwa 1st Road, Kwei-Shan, Tao-Yuan City, Taiwan, Republic Of China
| | - Yuling Lin
- Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, 259 Wen-Hwa 1st Road, Kwei-Shan, Tao-Yuan City, Taiwan, Republic Of China
| | - Yu-Shien Ko
- Division of Cardiology, Department of Internal Medicine, Chang Gung Memorial Hospital-Lin-kou, Chang Gung University, Tao-Yuan City, Taiwan, Republic Of China
| | - Jong-Shyan Wang
- Healthy Aging Research Center, Graduate Institute of Rehabilitation Science, Medical College, Chang Gung University, Tao-Yuan City, Taiwan, Republic Of China
| | - Vincent Hung-Shu Chang
- Program for Translation Medicine, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan, Republic Of China
| | - Jong-Hwei S Pang
- Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, 259 Wen-Hwa 1st Road, Kwei-Shan, Tao-Yuan City, Taiwan, Republic Of China. .,Department of Physical Medicine and Rehabilitation, Lin-Kou Medical Center, Chang Gung Memorial Hospital, Tao-Yuan City, Taiwan, Republic Of China.
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22
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Lojo N, Rasic Z, Zenko Sever A, Kolenc D, Vukusic D, Drmic D, Zoricic I, Sever M, Seiwerth S, Sikiric P. Effects of Diclofenac, L-NAME, L-Arginine, and Pentadecapeptide BPC 157 on Gastrointestinal, Liver, and Brain Lesions, Failed Anastomosis, and Intestinal Adaptation Deterioration in 24 Hour-Short-Bowel Rats. PLoS One 2016; 11:e0162590. [PMID: 27627764 PMCID: PMC5023193 DOI: 10.1371/journal.pone.0162590] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2015] [Accepted: 08/25/2016] [Indexed: 12/11/2022] Open
Abstract
Stable gastric pentadecapeptide BPC 157 was previously used to ameliorate wound healing following major surgery and counteract diclofenac toxicity. To resolve the increasing early risks following major massive small bowel resectioning surgery, diclofenac combined with nitric oxide (NO) system blockade was used, suggesting therapy with BPC 157 and the nitric oxide synthase (NOS substrate) L-arginine, is efficacious. Immediately after anastomosis creation, short-bowel rats were untreated or administered intraperitoneal diclofenac (12 mg/kg), BPC 157 (10 μg/kg or 10 ng/kg), L-NG-nitroarginine methyl ester (L-NAME, 5 mg/kg), L-arginine (100 mg/kg) alone or combined, and assessed 24 h later. Short-bowel rats exhibited poor anastomosis healing, failed intestine adaptation, and gastrointestinal, liver, and brain lesions, which worsened with diclofenac. This was gradually ameliorated by immediate therapy with BPC 157 and L-arginine. Contrastingly, NOS-blocker L-NAME induced further aggravation and lesions gradually worsened. Specifically, rats with surgery alone exhibited mild stomach/duodenum lesions, considerable liver lesions, and severe cerebral/hippocampal lesions while those also administered diclofenac showed widespread severe lesions in the gastrointestinal tract, liver, cerebellar nuclear/Purkinje cells, and cerebrum/hippocampus. Rats subjected to surgery, diclofenac, and L-NAME exhibited the mentioned lesions, worsening anastomosis, and macro/microscopical necrosis. Thus, rats subjected to surgery alone showed evidence of deterioration. Furtheremore, rats subjected to surgery and administered diclofenac showed worse symptoms, than the rats subjected to surgery alone did. Rats subjected to surgery combined with diclofenac and L-NAME showed the worst deterioration. Rats subjected to surgery exhibited habitual adaptation of the remaining small intestine, which was markedly reversed in rats subjected to surgery and diclofenac, and those with surgery, diclofenac, and L-NAME. BPC 157 completely ameliorated symptoms in massive intestinal resection-, massive intestinal resection plus diclofenac-, and massive intestinal resection plus diclofenac plus L-NAME-treated short bowel rats that presented with cyclooxygenase (COX)-NO-system inhibition. L-arginine ameliorated only L-NAME-induced aggravation of symptoms in rats subjected to massive intestinal resection and administered diclofenac plus L-NAME.
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Affiliation(s)
- Nermin Lojo
- Department of Pharmacology, School of Medicine, University of Zagreb, POB 916, Salata 11, 10000 Zagreb, Croatia
| | - Zarko Rasic
- Department of Pharmacology, School of Medicine, University of Zagreb, POB 916, Salata 11, 10000 Zagreb, Croatia
| | - Anita Zenko Sever
- Department of Pathology, School of Medicine, University of Zagreb, Salata 9, 10000 Zagreb, Croatia
| | - Danijela Kolenc
- Department of Pathology, School of Medicine, University of Zagreb, Salata 9, 10000 Zagreb, Croatia
| | - Darko Vukusic
- Department of Pharmacology, School of Medicine, University of Zagreb, POB 916, Salata 11, 10000 Zagreb, Croatia
| | - Domagoj Drmic
- Department of Pharmacology, School of Medicine, University of Zagreb, POB 916, Salata 11, 10000 Zagreb, Croatia
| | - Ivan Zoricic
- Department of Pharmacology, School of Medicine, University of Zagreb, POB 916, Salata 11, 10000 Zagreb, Croatia
| | - Marko Sever
- Department of Pharmacology, School of Medicine, University of Zagreb, POB 916, Salata 11, 10000 Zagreb, Croatia
| | - Sven Seiwerth
- Department of Pathology, School of Medicine, University of Zagreb, Salata 9, 10000 Zagreb, Croatia
| | - Predrag Sikiric
- Department of Pharmacology, School of Medicine, University of Zagreb, POB 916, Salata 11, 10000 Zagreb, Croatia
- * E-mail:
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23
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Zemba M, Cilic AZ, Balenovic I, Cilic M, Radic B, Suran J, Drmic D, Kokot A, Stambolija V, Murselovic T, Holjevac JK, Uzun S, Djuzel V, Vlainic J, Seiwerth S, Sikiric P. BPC 157 antagonized the general anaesthetic potency of thiopental and reduced prolongation of anaesthesia induced by L-NAME/thiopental combination. Inflammopharmacology 2015; 23:329-36. [PMID: 26563892 DOI: 10.1007/s10787-015-0249-9] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2015] [Accepted: 09/28/2015] [Indexed: 02/06/2023]
Abstract
AIM We hypothesized that certain effects of the general anaesthetic thiopental are dependent on NO-related mechanisms, which were consequently counteracted by stable gastric pentadecapeptide BPC 157. MAIN METHODS (1) All rats intraperitoneally received thiopental (20, 30, 40, and 50 mg/kg) while medication BPC 157 (10 μg/kg, 10 ng/kg, and 10 pg/kg) was given intraperitoneally at 5 min before thiopental. (2) To determine NO-related mechanisms, all rats received intraperitoneally thiopental 40 mg/kg while BPC 157 (10 μg/kg), L-NAME (10 mg/kg) and L-arginine (30 mg/kg) were applied alone and/or combined. BPC 157 was given at 25 min before thiopental while L-NAME, L-arginine, alone and/or combined, were applied at 20 min before thiopental. KEY FINDINGS (1) BPC 157 own effect on thiopental anaesthesia: BPC 157 (10 ng/kg and 10 μg/kg) caused a significant antagonism of general anaesthesia produced by thiopental with a parallel shift of the dose-response curve to the right. (2) L-NAME-L-arginine-BPC 157 interrelations: L-NAME: Thiopental-induced anaesthesia duration was tripled. L-arginine: Usual thiopental anaesthesia time was not influenced. Active only when given with L-NAME or BPC 157: potentiating effects of L-NAME were lessened, not abolished; shortening effect of BPC 157: abolished. BPC 157 and L-NAME: Potentiating effects of L-NAME were abolished. BPC 157 and L-NAME and L-arginine: BPC 157 +L-NAME +L-arginine rats exhibited values close to those in BPC 157 rats. SIGNIFICANCE Thiopental general anaesthesia is simultaneously manipulated in both ways with NO system activity modulation, L-NAME (prolongation) and BPC 157 (shortening/counteraction) and L-arginine (interference with L-NAME and BPC 157).
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Affiliation(s)
- Mladen Zemba
- Department of Pharmacology, School of Medicine, University of Zagreb, Salata 11, PO Box 916, 10000, Zagreb, Croatia
| | - Andrea Zemba Cilic
- Department of Pharmacology, School of Medicine, University of Zagreb, Salata 11, PO Box 916, 10000, Zagreb, Croatia
| | - Igor Balenovic
- Department of Pharmacology, School of Medicine, University of Zagreb, Salata 11, PO Box 916, 10000, Zagreb, Croatia
| | - Matija Cilic
- Department of Pharmacology, School of Medicine, University of Zagreb, Salata 11, PO Box 916, 10000, Zagreb, Croatia
| | - Bozo Radic
- Department of Pharmacology, School of Medicine, University of Zagreb, Salata 11, PO Box 916, 10000, Zagreb, Croatia
| | - Jelena Suran
- Department of Pharmacology, School of Medicine, University of Zagreb, Salata 11, PO Box 916, 10000, Zagreb, Croatia
| | - Domagoj Drmic
- Department of Pharmacology, School of Medicine, University of Zagreb, Salata 11, PO Box 916, 10000, Zagreb, Croatia
| | - Antonio Kokot
- Department of Pharmacology, School of Medicine, University of Zagreb, Salata 11, PO Box 916, 10000, Zagreb, Croatia
| | - Vasilije Stambolija
- Department of Pharmacology, School of Medicine, University of Zagreb, Salata 11, PO Box 916, 10000, Zagreb, Croatia
| | - Tamara Murselovic
- Department of Pharmacology, School of Medicine, University of Zagreb, Salata 11, PO Box 916, 10000, Zagreb, Croatia
| | - Jadranka Katancic Holjevac
- Department of Pharmacology, School of Medicine, University of Zagreb, Salata 11, PO Box 916, 10000, Zagreb, Croatia
| | - Sandra Uzun
- Department of Pharmacology, School of Medicine, University of Zagreb, Salata 11, PO Box 916, 10000, Zagreb, Croatia
| | - Viktor Djuzel
- Department of Pharmacology, School of Medicine, University of Zagreb, Salata 11, PO Box 916, 10000, Zagreb, Croatia
| | - Josipa Vlainic
- Department of Pharmacology, School of Medicine, University of Zagreb, Salata 11, PO Box 916, 10000, Zagreb, Croatia
| | - Sven Seiwerth
- Department of Pathology, School of Medicine, University of Zagreb, Zagreb, Croatia
| | - Predrag Sikiric
- Department of Pharmacology, School of Medicine, University of Zagreb, Salata 11, PO Box 916, 10000, Zagreb, Croatia.
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Stupnisek M, Franjic S, Drmic D, Hrelec M, Kolenc D, Radic B, Bojic D, Vcev A, Seiwerth S, Sikiric P. Pentadecapeptide BPC 157 reduces bleeding time and thrombocytopenia after amputation in rats treated with heparin, warfarin or aspirin. Thromb Res 2011; 129:652-9. [PMID: 21840572 DOI: 10.1016/j.thromres.2011.07.035] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2011] [Revised: 06/26/2011] [Accepted: 07/20/2011] [Indexed: 02/07/2023]
Abstract
Recently, in rat abdominal aorta terminoterminal-anastomosis the stable gastric pentadecapeptide BPC 157 prevents obstructive thrombus formation and rapidly destroys already formed obstructive thrombus. Also, BPC 157 wound healing may signify the clot as conductive matrix or "scaffold" to speed up wound healing process, and decrease bleeding. Here, in rats, BPC 157 (10 μg/kg, 10 ng/kg) improved always reduced bleeding time and amount of bleeding after (tail) amputation only, heparin (250 mg/kg, 25mg/kg, 10mg/kg i.v.), warfarin (1.5mg/kg i.g. once daily for 3 consecutive days), aspirin (0.1g/kg i.g. (once daily/3 consecutive days) or 1.0 g/kg i.p. once), and amputation associated with those agents application. BPC 157 counteracting regimens (i.v., i.p., i.g. (immediately after any challenge)) correspondingly follow the route of bleeding-agents application. All heparin-, warfarin-, and aspirin-rats and normal-rats that received BPC 157 exhibited lesser fall in platelets count. BPC 157 attenuated over-increased APTT-, TT-values in 10mg/kg heparin-rats, but did not influence heparin activity (anti-Xa test). Indicatively, unless counteracted in BPC 157 rats, excessive bleeding-acute thrombocytopenia (<20% of initial values in heparin-rats) approaches substantial fall in platelets count known in type II HIT. Also, BPC 157 markedly prolongs the survival time (heparin-rats, 25mg/kg, right foot amputation).
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Affiliation(s)
- Mirjana Stupnisek
- Department of Pharmacology and Pathology Medical Faculty University of Zagreb, Zagreb, Croatia
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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.
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Affiliation(s)
- Spomenko Ilic
- Department of Pharmacology and Pathology Medical Faculty University of Zagreb, Zagreb, Croatia
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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.
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Affiliation(s)
- Spomenko Ilic
- Department of Pharmacology and Pathology Medical Faculty, University of Zagreb, Zagreb, Croatia
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Novinscak T, Brcic L, Staresinic M, Jukic I, Radic B, Pevec D, Mise S, Tomasovic S, Brcic I, Banic T, Jakir A, Buljat G, Anic T, Zoricic I, Romic Z, Seiwerth S, Sikiric P. Gastric pentadecapeptide BPC 157 as an effective therapy for muscle crush injury in the rat. Surg Today 2008; 38:716-25. [PMID: 18668315 DOI: 10.1007/s00595-007-3706-2] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2007] [Accepted: 11/26/2007] [Indexed: 12/15/2022]
Abstract
PURPOSE Stable gastric pentadecapeptide BPC 157 accelerates the healing of a transected Achilles tendon and a transected quadriceps muscle. It may also be of clinical relevance as a systemic and local peptide treatment for crush injury of a major muscle, such as gastrocnemius muscle complex. BPC 157 is effective without a carrier, and it is presently undergoing trials for inflammatory bowel disease, and no toxicity has so far been reported. METHODS In crushed rats (force delivered 0.727 Ns/cm2), BPC 157 was applied either intraperitoneally or locally, as a thin cream layer, immediately after injury (sacrifice at 2 h), and once a day for 14 days. RESULTS BPC 157 improved muscle healing, macroscopically (less hematoma and edema, no post-injury leg contracture), microscopically, functionally, and also based on enzyme activity (creatine kinase, lactate dehydrogenase, aspartate aminotransferase, alanine aminotransferase). CONCLUSION BPC 157, at all investigated intervals, given locally or intraperitoneally, accelerated post-injury muscle healing and also helped to restore the full function.
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Affiliation(s)
- Tomislav Novinscak
- Department of Pharmacology, Institute of Pathology, University of Zagreb Medical School, Salata 11, 10 000, Zagreb, Croatia
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Staresinic M, Petrovic I, Novinscak T, Jukic I, Pevec D, Suknaic S, Kokic N, Batelja L, Brcic L, Boban-Blagaic A, Zoric Z, Ivanovic D, Ajduk M, Sebecic B, Patrlj L, Sosa T, Buljat G, Anic T, Seiwerth S, Sikiric P. Effective therapy of transected quadriceps muscle in rat: Gastric pentadecapeptide BPC 157. J Orthop Res 2006; 24:1109-17. [PMID: 16609979 DOI: 10.1002/jor.20089] [Citation(s) in RCA: 40] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
We report complete transection of major muscle and the systemic peptide treatment that induces healing of quadriceps muscle promptly and then maintains the healing with functional restoration. Initially, stable gastric pentadecapeptide BPC 157 (GEPPPGKPADDAGLV, M.W. 1419, PL-10, PLD-116, PL 14736 Pliva, Croatia; in trials for inflammatory bowel disease; wound treatment; no toxicity reported; effective alone without carrier) also superiorly accelerates the healing of transected Achilles tendon. Regularly, quadriceps muscle completely transected transversely 1.0 cm proximal to patella presents a definitive defect that cannot be compensated in rat. BPC 157 (10 microg, 10 ng, 10 pg/kg) is given intraperitoneally, once daily; the first application 30 min posttransection, the final 24 h before sacrifice. It consistently improves muscle healing throughout the whole 72-day period. Improved are: (i) biomechanic (load of failure increased); (ii) function (walking recovery and extensor postural thrust/motor function index returned toward normal healthy values); (iii) microscopy/immunochemistry [i.e., mostly muscle fibers connect muscle segments; absent gap; significant desmin positivity for ongoing regeneration of muscle; larger myofibril diameters on both sides, distal and proximal (normal healthy rat-values reached)]; (iv) macroscopic presentation (stumps connected; subsequently, atrophy markedly attenuated; finally, presentation close to normal noninjured muscle, no postsurgery leg contracture). Thus, posttransection healing-consistently improved-may suggest this peptide therapeutic application in muscle disorders.
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Affiliation(s)
- Mario Staresinic
- Department of Pharmacology, School of Medicine, University of Zagreb, Salata 11, P.O.B. 916, 10000 Zagreb, Croatia
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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.
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Affiliation(s)
- Alenka Boban Blagaic
- Department of Pharmacology Medical Faculty University of Zagreb, Salata 11, P.O. Box 916, 10000 Zagreb, Croatia
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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.
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Affiliation(s)
- Xiao-Chang Xue
- Biotechnology Centre, Fourth Military Medical University, 169 West Changle Road, Xi'an 710032, Shaanxi Province, China.
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Sikiric P, Seiwerth S, Mise S, Staresinic M, Bedekovic V, Zarkovic N, Borovic S, Gjurasin M, Boban-Blagaic A, Batelja L, Rucman R, Anic T. Corticosteroid-impairment of healing and gastric pentadecapeptide BPC-157 creams in burned mice. Burns 2003; 29:323-34. [PMID: 12781609 DOI: 10.1016/s0305-4179(03)00004-4] [Citation(s) in RCA: 37] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
The amelioration of corticosteroid-impairment of healing by a stable gastric pentadecapeptide BPC-157 (GEPPPGKPADDAGLV, M(w) 1419, currently in early clinical trials for inflammatory bowel disease) was studied in thermally injured mice. Its effects on corticosteroid impaired healing of deep partial skin thickness burns, and burn-gastric lesions were investigated. Male NMRI-Hannover mice (sacrificed at 1-3,7,14 and 21 days following burning 20% of total burn area at the back (open flame for 7s) received intraperitoneally (per kg bw) 6alpha-methylprednisolone (Depo-medrol, 1.0 or 10.0mg), or an equal volume of saline (5.0 ml), once daily, first application 30 min after injury, last 24h before sacrifice. The injury was subsequently treated by topical application of a thin layer of pentadecapeptide BPC-157 cream at three different levels a neutral cream of no treatment. Pentadecapeptide BPC-157 consistently improved given burn healing (both microscopical and tensionmetry assessment), and counteracted corticosteroid-impairment of burn healing. In burn-gastric lesions investigation of the effects of BPC showed an anti-ulcer effect of its own in burned non-corticosteroid-treated mice and potentiated the anti-ulcer effect observed in 6alpha-methylprednisolone-treated mice. Pentadecapeptide BPC-157 inhibited corticosteroid immunosuppression. In vitro, in spleenic cells assessment, animals (sacrificed at day 21) treated with 6alpha-methylprednisolone 1mg showed decreased reactivity to nitrogen in comparison with control, healthy animals, while the addition of BPC-157 (1 microg/g cream) returned cell reactivity to values noted in control healthy animals.
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Affiliation(s)
- P Sikiric
- Department of Pharmacology Medical Faculty, University of Zagreb, Salta 11, PO Box 916, Zagreb 10000, Croatia.
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Prkacin I, Aralica G, Perovic D, Separovic J, Gjurasin M, Lovric-Bencic M, Stancic-Rokotov D, Ziger T, Anic T, Sikiric P, Seiwerth S, Staresinic M, Mise S, Rotkvic I, Jagic V, Rucman R, Petek M, Turkovic B, Marovic A, Sjekavica I, Sebecic B, Boban-Blagaic A, Ivasovic Z. Chronic cytoprotection: pentadecapeptide BPC 157, ranitidine and propranolol prevent, attenuate and reverse the gastric lesions appearance in chronic alcohol drinking rats. JOURNAL OF PHYSIOLOGY, PARIS 2001; 95:295-301. [PMID: 11595453 DOI: 10.1016/s0928-4257(01)00041-9] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Unlike severe gastric damage acutely induced by ethanol administration in rat, the ulcerogenic effect of chronic alcohol administration (3.03 g/kg b.w. or 7.28 g/kg b.w.) given in drinking water, producing liver lesions and portal hypertension, is far less investigated. Therefore, focus was on the antiulcer effect of the gastric pentadecapeptide BPC 157, GEPPPGKPADDAGLV, M.W. 1419, known to have a beneficial effect in variety of gastrointestinal lesions models (10 microg or 10 ng/kg b.w. i.p. or i.g.), ranitidine (10 mg/kg b.w. i.g.) and propranol (10 mg/kg b.w. i.g.) or saline (5 ml/kg b.w. i.p./i.g.; control). They were given once daily (1) throughout 10 days preceding alcohol consumption, (2) since beginning of alcohol drinking till the end of the study, (3) throughout the last month of alcohol consumption, 2 months after alcohol drinking had been initiated. Gastric lesions were assessed, at the end of 3 months drinking [(1), (2)] or with respect to therapeutic effect of medication before medication or at the end of therapy. Pentadecapeptide BPC 157, ranitidine and propranolol may prevent gastric lesion development if given prophylactically, before alcohol drinking. Likewise, they attenuate the lesion appearance given once daily throughout the drinking period. Importantly, when given therapeutically, they may antagonize otherwise pertinent lesion presence in stomach mucosa of the drinking rats. Thus, these results demonstrate that pentadecapeptide BPC 157, ranitidine and propranol may prevent, attenuate or reverse the gastric lesions appearance in chronically alcohol drinking rats, and may be used for further therapy, while the other studies showed that their effect (except to ranitidine) is parallel with their beneficial effect on liver lesion and portal hypertension.
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Affiliation(s)
- I Prkacin
- Department of Pharmacology, Medical Faculty University of Zagreb, Salata 11, PO Box 916, Zagreb, Croatia
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