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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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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; 16:676. [PMID: 37242459 PMCID: PMC10224484 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 (L.B.O.)
| | - Slaven Gojkovic
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia (L.B.O.)
| | - Ivan Krezic
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia (L.B.O.)
| | - Ivan Maria Smoday
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia (L.B.O.)
| | - Luka Kalogjera
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia (L.B.O.)
| | - Helena Zizek
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia (L.B.O.)
| | - Katarina Oroz
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia (L.B.O.)
| | - Hrvoje Vranes
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia (L.B.O.)
| | - Vlasta Vukovic
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia (L.B.O.)
| | - May Labidi
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia (L.B.O.)
| | - Sanja Strbe
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia (L.B.O.)
| | - Lidija Baketic Oreskovic
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia (L.B.O.)
| | - 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 (L.B.O.)
| | - Ivan Barisic
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia (L.B.O.)
| | - 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 (L.B.O.)
| | - Alenka Boban Blagaic
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia (L.B.O.)
| | - Sven Seiwerth
- Department of Pathology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia
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Staresinic M, Japjec M, Vranes H, Prtoric A, Zizek H, Krezic I, Gojkovic S, Smoday IM, Oroz K, Staresinic E, Dretar V, Yago H, Milavic M, Sikiric S, Lovric E, Batelja Vuletic L, Simeon P, Dobric I, Strbe S, Kokot A, Vlainic J, Blagaic AB, Skrtic A, Seiwerth S, Sikiric P. Stable Gastric Pentadecapeptide BPC 157 and Striated, Smooth, and Heart Muscle. Biomedicines 2022; 10:3221. [PMID: 36551977 PMCID: PMC9775659 DOI: 10.3390/biomedicines10123221] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2022] [Revised: 11/29/2022] [Accepted: 12/01/2022] [Indexed: 12/14/2022] Open
Abstract
First, we review the definitively severed myotendinous junction and recovery by the cytoprotective stable gastric pentadecapeptide BPC 157 therapy, its healing that might combine both transected and detached tendon and transected muscle, ligament and bone injuries, applied alone, as native peptide therapy, effective in rat injury, given intraperitoneally or in drinking water or topically, at the site of injury. As a follow up, we reviewed that with the BPC 157 therapy, its cytoprotective ability to organize simultaneous healing of different tissues of and full recovery of the myotendinous junction might represent the particular muscle therapy against distinctive etiopathology muscle disabilities and weakness. In this, BPC 157 therapy might recover many of muscle disabilities (i.e., succinylcholine, vascular occlusion, spinal cord compression, stroke, traumatic brain injury, severe electrolyte disturbances, neurotoxins, neuroleptics, alcohol, serotonin syndrome and NO-system blockade and tumor-cachexia). These might provide practical realization of the multimodal muscle-axis impact able to react depending on the condition and the given agent(s) and the symptoms distinctively related to the prime injurious cause symptoms in the wide healing concept, the concept of cytoprotection, in particular. Further, the BPC 157 therapy might be the recovery for the disabled heart functioning, and disabled smooth muscle functioning (various sphincters function recovery). Finally, BPC 157, native and stable in human gastric juice, might be a prototype of anti-ulcer cytoprotective peptide for the muscle therapy with high curing potential (very safe profile (lethal dose not achieved), with suited wide effective range (µg-ng regimens) and ways of application).
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Affiliation(s)
- Mario Staresinic
- Department of Surgery, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia
| | - Mladen Japjec
- 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
| | - Andreja Prtoric
- 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
| | - Ivan Krezic
- 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 Maria Smoday
- 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
| | - Eva Staresinic
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia
| | - Vilim Dretar
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia
| | - Haidi Yago
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia
| | - Marija Milavic
- Department of Pathology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia
| | - Suncana Sikiric
- Department of Pathology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia
| | - Eva Lovric
- Department of Pathology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia
| | | | - Paris Simeon
- Department of Endodontics and Restorative Dentistry, School of Dental Medicine, University of Zagreb, 10000 Zagreb, Croatia
| | - Ivan Dobric
- Department of Surgery, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia
| | - Sanja Strbe
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia
| | - Antonio Kokot
- Department of Anatomy and Neuroscience, School of Medicine, J.J. Strossmayer University of Osijek, 31000 Osijek, Croatia
| | - Josipa Vlainic
- Laboratory for Advanced Genomics, Division of Molecular Medicine, lnstitute Ruder Boskovic, 10000 Zagreb, Croatia
| | - Alenka Boban Blagaic
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 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
| | - Predrag Sikiric
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia
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Vukojević J, Milavić M, Perović D, Ilić S, Čilić AZ, Đuran N, Štrbe S, Zoričić Z, Filipčić I, Brečić P, Seiverth S, Sikirić P. Pentadecapeptide BPC 157 and the central nervous system. Neural Regen Res 2022; 17:482-487. [PMID: 34380875 PMCID: PMC8504390 DOI: 10.4103/1673-5374.320969] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2020] [Revised: 12/08/2020] [Accepted: 03/08/2021] [Indexed: 11/04/2022] Open
Abstract
We reviewed the pleiotropic beneficial effects of the stable gastric pentadecapeptide BPC 157, three very recent demonstrations that may be essential in the gut-brain and brain-gut axis operation, and therapy application in the central nervous system disorders, in particular. Firstly, given in the reperfusion, BPC 157 counteracted bilateral clamping of the common carotid arteries-induced stroke, sustained brain neuronal damages were resolved in rats as well as disturbed memory, locomotion, and coordination. This therapy effect supports particular gene expression in hippocampal tissues that appeared in BPC 157-treated rats. Secondly, there are L-NG-nitro arginine methyl ester (L-NAME)- and haloperidol-induced catalepsy as well as the rat acute and chronic models of 'positive-like' schizophrenia symptoms, that BPC 157 counteracted, and resolved the complex relationship of the nitric oxide-system with amphetamine and apomorphine (dopamine agents application), MK-801 (non-competitive antagonist of the N-methyl-D-aspartate receptor) and chronic methamphetamine administration (to induce sensitivity). Thirdly, after rat spinal cord compression, there were advanced healing and functional recovery (counteracted tail paralysis). Likewise, in BPC 157 therapy, there is specific support for each of these topics: counteracted encephalopathies; alleviated vascular occlusion disturbances (stroke); counteracted dopamine disturbances (dopamine receptors blockade, receptors super sensitivity development, or receptor activation, over-release, nigrostriatal damage, vesicles depletion), and nitric oxide-system disturbances ("L-NAME non-responsive, L-arginine responsive," and "L-NAME responsive, L-arginine responsive") (schizophrenia therapy); inflammation reduction, nerve recovery in addition to alleviated hemostasis and vessels function after compression (spinal cord injury therapy). Thus, these disturbances may be all resolved within the same agent's beneficial activity, i.e., the stable gastric pentadecapeptide BPC 157.
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Affiliation(s)
- Jakša Vukojević
- Department of Pharmacology, Medical School, University of Zagreb, Zagreb, Croatia
| | - Marija Milavić
- Department of Pathology, Medical School, University of Zagreb, Zagreb, Croatia
| | - Darko Perović
- Department of Pharmacology, Medical School, University of Zagreb, Zagreb, Croatia
| | - Spomenko Ilić
- Department of Pharmacology, Medical School, University of Zagreb, Zagreb, Croatia
| | | | - Nataša Đuran
- University Psychiatric Hospital “Vrapče”, Zagreb, Croatia
| | - Sanja Štrbe
- University Clinical Hospital Center “Zagreb”, Zagreb, Croatia
| | - Zoran Zoričić
- University Clinical Hospital Center “Sestre Milosrdnice”, Zagreb, Croatia
| | | | - Petrana Brečić
- University Psychiatric Hospital “Vrapče”, Zagreb, Croatia
| | - Sven Seiverth
- Department of Pathology, Medical School, University of Zagreb, Zagreb, Croatia
| | - Predrag Sikirić
- Department of Pharmacology, Medical School, University of Zagreb, Zagreb, Croatia
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Jung YH, Kim H, Kim H, Kim E, Baik J, Kang H. The anti-nociceptive effect of BPC-157 on the incisional pain model in rats. J Dent Anesth Pain Med 2022; 22:97-105. [PMID: 35449779 PMCID: PMC8995671 DOI: 10.17245/jdapm.2022.22.2.97] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2022] [Revised: 01/23/2022] [Accepted: 01/24/2022] [Indexed: 11/15/2022] Open
Affiliation(s)
- Young-Hoon Jung
- Department of Anesthesia and Pain Medicine, Pusan National University Hospital, Busan, Korea
| | - Haekyu Kim
- Department of Anesthesia and Pain Medicine, Pusan National University Hospital, Busan, Korea
- Department of Anesthesia and Pain Medicine, School of Medicine, Pusan National University, Busan, Korea
| | - Hyaejin Kim
- Department of Anesthesia and Pain Medicine, Pusan National University Hospital, Busan, Korea
| | - Eunsoo Kim
- Department of Anesthesia and Pain Medicine, Pusan National University Hospital, Busan, Korea
- Department of Anesthesia and Pain Medicine, School of Medicine, Pusan National University, Busan, Korea
| | - Jiseok Baik
- Department of Anesthesia and Pain Medicine, Pusan National University Hospital, Busan, Korea
- Department of Anesthesia and Pain Medicine, School of Medicine, Pusan National University, Busan, Korea
| | - Hyunjong Kang
- Department of Anesthesia and Pain Medicine, Pusan National University Hospital, Busan, Korea
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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] [Key Words] [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
| | - 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
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Seiwerth S, Milavic M, Vukojevic J, Gojkovic S, Krezic I, Vuletic LB, Pavlov KH, Petrovic A, Sikiric S, Vranes H, Prtoric A, Zizek H, Durasin T, Dobric I, Staresinic M, Strbe S, Knezevic M, Sola M, Kokot A, Sever M, Lovric E, Skrtic A, Blagaic AB, Sikiric P. Stable Gastric Pentadecapeptide BPC 157 and Wound Healing. Front Pharmacol 2021; 12:627533. [PMID: 34267654 PMCID: PMC8275860 DOI: 10.3389/fphar.2021.627533] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2020] [Accepted: 02/03/2021] [Indexed: 12/11/2022] Open
Abstract
Significance: The antiulcer peptide, stable gastric pentadecapeptide BPC 157 (previously employed in ulcerative colitis and multiple sclerosis trials, no reported toxicity (LD1 not achieved)), is reviewed, focusing on the particular skin wound therapy, incisional/excisional wound, deep burns, diabetic ulcers, and alkali burns, which may be generalized to the other tissues healing. Recent Advances: BPC 157 has practical applicability (given alone, with the same dose range, and same equipotent routes of application, regardless the injury tested). Critical Issues: By simultaneously curing cutaneous and other tissue wounds (colocutaneous, gastrocutaneous, esophagocutaneous, duodenocutaneous, vesicovaginal, and rectovaginal) in rats, the potency of BPC 157 is evident. Healing of the wounds is accomplished by resolution of vessel constriction, the primary platelet plug, the fibrin mesh which acts to stabilize the platelet plug, and resolution of the clot. Thereby, BPC 157 is effective in wound healing much like it is effective in counteracting bleeding disorders, produced by amputation, and/or anticoagulants application. Likewise, BPC 157 may prevent and/or attenuate or eliminate, thus, counteract both arterial and venous thrombosis. Then, confronted with obstructed vessels, there is circumvention of the occlusion, which may be the particular action of BPC 157 in ischemia/reperfusion. Future Directions: BPC 157 rapidly increases various genes expression in rat excision skin wound. This would define the healing in the other tissues, that is, gastrointestinal tract, tendon, ligament, muscle, bone, nerve, spinal cord, cornea (maintained transparency), and blood vessels, seen with BPC 157 therapy.
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Affiliation(s)
- Sven Seiwerth
- Department of Pathology, School of Medicine, University of Zagreb, Zagreb, Croatia
| | - Marija Milavic
- Department of Pathology, School of Medicine, University of Zagreb, Zagreb, Croatia
| | - Jaksa Vukojevic
- Department of Pharmacology, School of Medicine, University of Zagreb, Zagreb, Croatia
| | - Slaven Gojkovic
- Department of Pharmacology, School of Medicine, University of Zagreb, Zagreb, Croatia
| | - Ivan Krezic
- Department of Pharmacology, School of Medicine, University of Zagreb, Zagreb, Croatia
| | | | | | - Andrea Petrovic
- Department of Pathology, School of Medicine, University of Zagreb, Zagreb, Croatia
| | - Suncana Sikiric
- Department of Pathology, School of Medicine, University of Zagreb, Zagreb, Croatia
| | - Hrvoje Vranes
- Department of Pharmacology, School of Medicine, University of Zagreb, Zagreb, Croatia
| | - Andreja Prtoric
- Department of Surgery, School of Medicine, University of Zagreb, Zagreb, Croatia
| | - Helena Zizek
- Department of Pharmacology, School of Medicine, University of Zagreb, Zagreb, Croatia
| | - Tajana Durasin
- Department of Pharmacology, School of Medicine, University of Zagreb, Zagreb, Croatia
| | - Ivan Dobric
- Department of Surgery, School of Medicine, University of Zagreb, Zagreb, Croatia
| | - Mario Staresinic
- Department of Surgery, School of Medicine, University of Zagreb, Zagreb, Croatia
| | - Sanja Strbe
- Department of Pharmacology, School of Medicine, University of Zagreb, Zagreb, Croatia
| | - Mario Knezevic
- Department of Pharmacology, School of Medicine, University of Zagreb, Zagreb, Croatia
| | - Marija Sola
- Department of Pharmacology, School of Medicine, University of Zagreb, Zagreb, Croatia
| | - Antonio Kokot
- Department of Anatomy and Neuroscience, School of Medicine Osijek, University of Osijek, Osijek, Croatia
| | - Marko Sever
- Department of Surgery, School of Medicine, University of Zagreb, Zagreb, Croatia
| | - Eva Lovric
- Department of Pathology, School of Medicine, University of Zagreb, Zagreb, Croatia
| | - Anita Skrtic
- Department of Pathology, School of Medicine, University of Zagreb, Zagreb, Croatia
| | - Alenka Boban Blagaic
- Department of Pharmacology, School of Medicine, University of Zagreb, Zagreb, Croatia
| | - Predrag Sikiric
- Department of Pharmacology, School of Medicine, University of Zagreb, Zagreb, Croatia
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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; 9:609. [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] [Grants] [Track Full Text] [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.)
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Zemba Cilic A, Zemba M, Cilic M, Balenovic I, Strbe S, Ilic S, Vukojevic J, Zoricic Z, Filipcic I, Kokot A, Drmic D, Blagaic AB, Tvrdeic A, Seiwerth S, Sikiric P. Pentadecapeptide BPC 157 counteracts L-NAME-induced catalepsy. BPC 157, L-NAME, L-arginine, NO-relation, in the suited rat acute and chronic models resembling 'positive-like' symptoms of schizophrenia. Behav Brain Res 2021; 396:112919. [PMID: 32956773 DOI: 10.1016/j.bbr.2020.112919] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2019] [Revised: 08/15/2020] [Accepted: 09/14/2020] [Indexed: 12/13/2022]
Abstract
In the suited rat-models, we focused on the stable pentadecapeptide BPC 157, L-NAME, NOS-inhibitor, and L-arginine, NOS-substrate, relation, the effect on schizophrenia-like symptoms. Medication (mg/kg intraperitoneally) was L-NAME (5), L-arginine (100), BPC 157 (0.01), given alone and/or together, at 5 min before the challenge for the acutely disturbed motor activity (dopamine-indirect/direct agonists (amphetamine (3.0), apomorphine (2.5)), NMDA-receptor non-competitive antagonist (MK-801 (0.2)), or catalepsy, (dopamine-receptor antagonist haloperidol (2.0)). Alternatively, BPC 157 10 μg/kg was given immediately after L-NAME 40 mg/kg intraperitoneally. To induce or prevent sensitization, we used chronic methamphetamine administration, alternating 3 days during the first 3 weeks, and challenge after next 4 weeks, and described medication (L-NAME, L-arginine, BPC 157) at 5 min before the methamphetamine at the second and third week. Given alone, BPC 157 or L-arginine counteracted the amphetamine-, apomorphine-, and MK-801-induced effect, haloperidol-induced catalepsy and chronic methamphetamine-induced sensitization. L-NAME did not affect the apomorphine-, and MK-801-induced effects, haloperidol-induced catalepsy and chronic methamphetamine-induced sensitization, but counteracted the acute amphetamine-induced effect. In combinations (L-NAME + L-arginine), as NO-specific counteraction, L-NAME counteracts L-arginine-induced counteractions in the apomorphine-, MK-801-, haloperidol- and methamphetamine-rats, but not in amphetamine-rats. Unlike L-arginine, BPC 157 maintains its counteracting effect in the presence of the NOS-blockade (L-NAME + BPC 157) or NO-system-over-stimulation (L-arginine + BPC 157). Illustrating the BPC 157-L-arginine relationships, BPC 157 restored the antagonization (L-NAME + L-arginine + BPC 157) when it had been abolished by the co-administration of L-NAME with L-arginine (L-NAME + L-arginine). Finally, BPC 157 directly inhibits the L-NAME high dose-induced catalepsy. Further studies would determine precise BPC 157/dopamine/glutamate/NO-system relationships and clinical application.
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Affiliation(s)
- Andrea Zemba Cilic
- Departments of Pharmacology and Pathology, School of Medicine, University of Zagreb, Zagreb, Croatia
| | - Mladen Zemba
- Departments of Pharmacology and Pathology, School of Medicine, University of Zagreb, Zagreb, Croatia
| | - Matija Cilic
- Departments of Pharmacology and Pathology, School of Medicine, University of Zagreb, Zagreb, Croatia
| | - Igor Balenovic
- Departments of Pharmacology and Pathology, School of Medicine, University of Zagreb, Zagreb, Croatia
| | - Sanja Strbe
- Departments of Pharmacology and Pathology, School of Medicine, University of Zagreb, Zagreb, Croatia
| | - Spomenko Ilic
- Departments of Pharmacology and Pathology, School of Medicine, University of Zagreb, Zagreb, Croatia
| | - Jaksa Vukojevic
- Departments of Pharmacology and Pathology, School of Medicine, University of Zagreb, Zagreb, Croatia
| | - Zoran Zoricic
- Departments of Pharmacology and Pathology, School of Medicine, University of Zagreb, Zagreb, Croatia
| | - Igor Filipcic
- Departments of Pharmacology and Pathology, School of Medicine, University of Zagreb, Zagreb, Croatia
| | - Antonio Kokot
- Departments of Pharmacology and Pathology, School of Medicine, University of Zagreb, Zagreb, Croatia
| | - Domagoj Drmic
- Departments of Pharmacology and Pathology, School of Medicine, University of Zagreb, Zagreb, Croatia
| | - Alenka Boban Blagaic
- Departments of Pharmacology and Pathology, School of Medicine, University of Zagreb, Zagreb, Croatia
| | - Ante Tvrdeic
- Departments of Pharmacology and Pathology, School of Medicine, University of Zagreb, Zagreb, Croatia
| | - Sven Seiwerth
- Departments of Pharmacology and Pathology, School of Medicine, University of Zagreb, Zagreb, Croatia
| | - Predrag Sikiric
- Departments of Pharmacology and Pathology, School of Medicine, University of Zagreb, Zagreb, Croatia.
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Modulatory effects of BPC 157 on vasomotor tone and the activation of Src-Caveolin-1-endothelial nitric oxide synthase pathway. Sci Rep 2020; 10:17078. [PMID: 33051481 PMCID: PMC7555539 DOI: 10.1038/s41598-020-74022-y] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2019] [Accepted: 08/03/2020] [Indexed: 02/07/2023] Open
Abstract
BPC 157-activated endothelial nitric oxide synthase (eNOS) is associated with tissue repair and angiogenesis as reported in previous studies. However, how BPC 157 regulates the vasomotor tone and intracellular Src-Caveolin-1 (Cav-1)-eNOS signaling is not yet clear. The present study demonstrated a concentration-dependent vasodilation effect of BPC 157 in isolated rat aorta. Attenuation of this vasodilation effect in the absence of endothelium suggested an endothelium-dependent vasodilation effect of BPC 157. Although slightly increased vasorelaxation in aorta without endothelium was noticed at high concentration of BPC 157, there was no direct relaxation effect on three-dimensional model made of vascular smooth muscle cells. The vasodilation effect of BPC 157 was nitric oxide mediated because the addition of L-NAME or hemoglobin inhibited the vasodilation of aorta. Nitric oxide generation was induced by BPC 157 as detected by intracellular DFA-FM DA labeling which was capable of promoting the migration of vascular endothelial cells. BPC 157 enhanced the phosphorylation of Src, Cav-1 and eNOS which was abolished by pretreatment with Src inhibitor, confirming the upstream role of Src in this signal pathway. Activation of eNOS required the released binding with Cav-1 in advance. Co-immunoprecipitation analysis revealed that BPC 157 could reduce the binding between Cav-1 and eNOS. Together, the present study demonstrates that BPC 157 can modulate the vasomotor tone of an isolated aorta in a concentration- and nitric oxide-dependent manner. BPC 157 can induce nitric oxide generation likely through the activation of Src-Cav-1-eNOS pathway.
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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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Sikiric P, Drmic D, Sever M, Klicek R, Blagaic AB, Tvrdeic A, Kralj T, Kovac KK, Vukojevic J, Siroglavic M, Gojkovic S, Krezic I, Pavlov KH, Rasic D, Mirkovic I, Kokot A, Skrtic A, Seiwerth S. Fistulas Healing. Stable Gastric Pentadecapeptide BPC 157 Therapy. Curr Pharm Des 2020; 26:2991-3000. [PMID: 32329684 DOI: 10.2174/1381612826666200424180139] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2020] [Accepted: 04/16/2020] [Indexed: 02/07/2023]
Abstract
This review is focused on the healing of fistulas and stable gastric pentadecapeptide BPC 157. Assuming that the healing of the various wounds is essential also for the gastrointestinal fistulas healing, the healing effect on fistulas in rats, consistently noted with the stable gastric pentadecapeptide BPC 157, may raise several interesting possibilities. BPC 157 is originally an anti-ulcer agent, native to and stable in human gastric juice (for more than 24 h). Likely, it is a novel mediator of Robert's cytoprotection maintaining gastrointestinal mucosal integrity. Namely, it is effective in the whole gastrointestinal tract, and heals various wounds (i.e., skin, muscle, tendon, ligament, bone; ulcers in the entire gastrointestinal tract; corneal ulcer); LD1 is not achieved. It is used in ulcerative colitis clinical trials, and now in multiple sclerosis, and addressed in several reviews. Therefore, it is not surprising that BPC 157 has documented consistent healing of the various gastrointestinal fistulas, external (esophagocutaneous, gastrocutaneous, duodenocutaneous, colocutaneous) and internal (colovesical, rectovaginal). Taking fistulas as a pathological connection, this rescue is verified with the beneficial effects in rats with the various gastrointestinal anastomoses, esophagogastric, jejunoileal, colo-colonic, ileoileal, esophagojejunal, esophagoduodenal, and gastrojejunal. This beneficial effect occurs equally when the gastrointestinal anastomoses are impaired with the application of NSAIDs, cysteamine, large bowel resection, as well as concomitant esophageal, gastric, and duodenal lesions and/or ulcerative colitis presentation, short bowel syndrome progression, liver and brain disturbances presentation. Particular aspects of the BPC 157 healing of the fistulas are especially emphasized.
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Affiliation(s)
- Predrag Sikiric
- Departments of Pharmacology and Pathology, School of Medicine, University of Zagreb, Salata 11, POB 916, 10000 Zagreb, Croatia
| | - Domagoj Drmic
- Departments of Pharmacology and Pathology, School of Medicine, University of Zagreb, Salata 11, POB 916, 10000 Zagreb, Croatia
| | - Marko Sever
- Departments of Pharmacology and Pathology, School of Medicine, University of Zagreb, Salata 11, POB 916, 10000 Zagreb, Croatia
| | - Robert Klicek
- Departments of Pharmacology and Pathology, School of Medicine, University of Zagreb, Salata 11, POB 916, 10000 Zagreb, Croatia
| | - Alenka B Blagaic
- Departments of Pharmacology and Pathology, School of Medicine, University of Zagreb, Salata 11, POB 916, 10000 Zagreb, Croatia
| | - Ante Tvrdeic
- Departments of Pharmacology and Pathology, School of Medicine, University of Zagreb, Salata 11, POB 916, 10000 Zagreb, Croatia
| | - Tamara Kralj
- Departments of Pharmacology and Pathology, School of Medicine, University of Zagreb, Salata 11, POB 916, 10000 Zagreb, Croatia
| | - Katarina K Kovac
- Departments of Pharmacology and Pathology, School of Medicine, University of Zagreb, Salata 11, POB 916, 10000 Zagreb, Croatia
| | - Jaksa Vukojevic
- Departments of Pharmacology and Pathology, School of Medicine, University of Zagreb, Salata 11, POB 916, 10000 Zagreb, Croatia
| | - Marko Siroglavic
- Departments of Pharmacology and Pathology, School of Medicine, University of Zagreb, Salata 11, POB 916, 10000 Zagreb, Croatia
| | - Slaven Gojkovic
- Departments of Pharmacology and Pathology, School of Medicine, University of Zagreb, Salata 11, POB 916, 10000 Zagreb, Croatia
| | - Ivan Krezic
- Departments of Pharmacology and Pathology, School of Medicine, University of Zagreb, Salata 11, POB 916, 10000 Zagreb, Croatia
| | - Katarina H Pavlov
- Departments of Pharmacology and Pathology, School of Medicine, University of Zagreb, Salata 11, POB 916, 10000 Zagreb, Croatia
| | - Domagoj Rasic
- Departments of Pharmacology and Pathology, School of Medicine, University of Zagreb, Salata 11, POB 916, 10000 Zagreb, Croatia
| | - Ivan Mirkovic
- Departments of Pharmacology and Pathology, School of Medicine, University of Zagreb, Salata 11, POB 916, 10000 Zagreb, Croatia
| | - Antonio Kokot
- Departments of Pharmacology and Pathology, School of Medicine, University of Zagreb, Salata 11, POB 916, 10000 Zagreb, Croatia
| | - Anita Skrtic
- Departments of Pharmacology and Pathology, School of Medicine, University of Zagreb, Salata 11, POB 916, 10000 Zagreb, Croatia
| | - Sven Seiwerth
- Departments of Pharmacology and Pathology, School of Medicine, University of Zagreb, Salata 11, POB 916, 10000 Zagreb, Croatia
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Drmic D, Samara M, Vidovic T, Malekinusic D, Antunovic M, Vrdoljak B, Ruzman J, Milkovic Perisa M, Horvat Pavlov K, Jeyakumar J, Seiwerth S, Sikiric P. Counteraction of perforated cecum lesions in rats: Effects of pentadecapeptide BPC 157, L-NAME and L-arginine. World J Gastroenterol 2018; 24:5462-5476. [PMID: 30622376 PMCID: PMC6319139 DOI: 10.3748/wjg.v24.i48.5462] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/20/2018] [Revised: 12/05/2018] [Accepted: 12/19/2018] [Indexed: 02/06/2023] Open
Abstract
AIM To study the counteraction of perforated cecum lesion using BPC 157 and nitric oxide (NO) system agents. METHODS Alongside with the agents' application (after 1 min, medication (/kg, 10 mL/2 min bath/rat) includes: BPC 157 (10 μg), L-NAME (5 mg), L-arginine (100mg) alone or combined, and saline baths (controls)) on the rat perforate cecum injury, we continuously assessed the gross reappearance of the vessels (USB microcamera) quickly propagating toward the defect at the cecum surface, defect contraction, bleeding attenuation, MDA- and NO-levels in cecum tissue at 15 min, and severity of cecum lesions and adhesions at 1 and 7 d. RESULTS Post-injury, during/after a saline bath, the number of vessels was significantly reduced, the defect was slightly narrowed, bleeding was significant and MDA-levels increased and NO-levels decreased. BPC 157 bath: the vessel presentation was markedly increased, the defect was noticeably narrowed, the bleeding time was shortened and MDA- and NO-levels remained normal. L-NAME: reduced vessel presentation but not more than the control, did not change defect and shortened bleeding. L-arginine: exhibited less vessel reduction, did not change the defect and prolonged bleeding. In combination, mutual counteraction occurred (L-NAME + L-arginine) or the presentation was similar to that of BPC 157 rats (BPC 157 + L-NAME; BPC 157 + L-arginine; BPC 157 + L-NAME + L-arginine), except the defect did not change. Thereby at day 1 and 7, saline, L-NAME, L-arginine and L-NAME + L-arginine failed (defect was still open and large adhesions present). CONCLUSION The therapeutic effect was achieved with BPC 157 alone or in combination with L-NAME and L-arginine as it was able to consolidate the stimulating and inhibiting effects of the NO-system towards more effective healing recruiting vessels.
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Affiliation(s)
- Domagoj Drmic
- Departments of Pharmacology and Pathology, Medical Faculty University of Zagreb, Zagreb 10000, Croatia
| | - Mariam Samara
- Departments of Pharmacology and Pathology, Medical Faculty University of Zagreb, Zagreb 10000, Croatia
| | - Tinka Vidovic
- Departments of Pharmacology and Pathology, Medical Faculty University of Zagreb, Zagreb 10000, Croatia
| | - Dominik Malekinusic
- Departments of Pharmacology and Pathology, Medical Faculty University of Zagreb, Zagreb 10000, Croatia
| | - Marko Antunovic
- Departments of Pharmacology and Pathology, Medical Faculty University of Zagreb, Zagreb 10000, Croatia
| | - Borna Vrdoljak
- Departments of Pharmacology and Pathology, Medical Faculty University of Zagreb, Zagreb 10000, Croatia
| | - Jelena Ruzman
- Departments of Pharmacology and Pathology, Medical Faculty University of Zagreb, Zagreb 10000, Croatia
| | - Marija Milkovic Perisa
- Departments of Pharmacology and Pathology, Medical Faculty University of Zagreb, Zagreb 10000, Croatia
| | - Katarina Horvat Pavlov
- Departments of Pharmacology and Pathology, Medical Faculty University of Zagreb, Zagreb 10000, Croatia
| | - Jerusha Jeyakumar
- Departments of Pharmacology and Pathology, Medical Faculty University of Zagreb, Zagreb 10000, Croatia
| | - Sven Seiwerth
- Departments of Pharmacology and Pathology, Medical Faculty University of Zagreb, Zagreb 10000, Croatia
| | - Predrag Sikiric
- Departments of Pharmacology and Pathology, Medical Faculty University of Zagreb, Zagreb 10000, Croatia
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Amic F, Drmic D, Bilic Z, Krezic I, Zizek H, Peklic M, Klicek R, Pajtak A, Amic E, Vidovic T, Rakic M, Milkovic Perisa M, Horvat Pavlov K, Kokot A, Tvrdeic A, Boban Blagaic A, Zovak M, Seiwerth S, Sikiric P. Bypassing major venous occlusion and duodenal lesions in rats, and therapy with the stable gastric pentadecapeptide BPC 157, L-NAME and L-arginine. World J Gastroenterol 2018; 24:5366-5378. [PMID: 30598581 PMCID: PMC6305534 DOI: 10.3748/wjg.v24.i47.5366] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/08/2018] [Revised: 11/26/2018] [Accepted: 11/30/2018] [Indexed: 02/06/2023] Open
Abstract
AIM To investigate whether duodenal lesions induced by major venous occlusions can be attenuated by BPC 157 regardless nitric oxide (NO) system involvement. METHODS Male Wistar rats underwent superior anterior pancreaticoduodenal vein (SAPDV)-ligation and were treated with a bath at the ligated SAPDV site (BPC 157 10 μg, 10 ng/kg per 1 mL bath/rat; L-NAME 5 mg/kg per 1 mL bath/rat; L-arginine 100 mg/kg per 1 mL bath/rat, alone and/or together; or BPC 157 10 μg/kg instilled into the rat stomach, at 1 min ligation-time). We recorded the vessel presentation (filled/appearance or emptied/disappearance) between the 5 arcade vessels arising from the SAPDV on the ventral duodenum side, the inferior anterior pancreaticoduodenal vein (IAPDV) and superior mesenteric vein (SMV) as bypassing vascular pathway to document the duodenal lesions presentation; increased NO- and oxidative stress [malondialdehyde (MDA)]-levels in duodenum. RESULTS Unlike the severe course in the SAPDV-ligated controls, after BPC 157 application, the rats exhibited strong attenuation of the mucosal lesions and serosal congestion, improved vessel presentation, increased interconnections, increased branching by more than 60% from the initial value, the IAPDV and SMV were not congested. Interestingly, after 5 min and 30 min of L-NAME and L-arginine treatment alone, decreased mucosal and serosal duodenal lesions were observed; their effect was worsened at 24 h, and no effect on the collateral vessels and branching was seen. Together, L-NAME+L-arginine antagonized each other's response, and thus, there was an NO-related effect. With BPC 157, all SAPDV-ligated rats receiving L-NAME and/or L-arginine appeared similar to the rats treated with BPC 157 alone. Also, BPC 157 in SAPDV-ligated rats normalized levels of NO and MDA, two oxidative stress markers, in duodenal tissues. CONCLUSION BPC 157, rapidly bypassing occlusion, rescued the original duodenal flow through IAPDV to SMV flow, an effect related to the NO system and reduction of free radical formation.
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Affiliation(s)
- Fedor Amic
- Department of Pharmacology, Medical Faculty, University of Zagreb, Zagreb 10000, Croatia
- Department of Pathology, Medical Faculty, University of Zagreb, Zagreb 10000, Croatia
| | - Domagoj Drmic
- Department of Pharmacology, Medical Faculty, University of Zagreb, Zagreb 10000, Croatia
- Department of Pathology, Medical Faculty, University of Zagreb, Zagreb 10000, Croatia
| | - Zdenko Bilic
- Department of Pharmacology, Medical Faculty, University of Zagreb, Zagreb 10000, Croatia
- Department of Pathology, Medical Faculty, University of Zagreb, Zagreb 10000, Croatia
| | - Ivan Krezic
- Department of Pharmacology, Medical Faculty, University of Zagreb, Zagreb 10000, Croatia
- Department of Pathology, Medical Faculty, University of Zagreb, Zagreb 10000, Croatia
| | - Helena Zizek
- Department of Pharmacology, Medical Faculty, University of Zagreb, Zagreb 10000, Croatia
- Department of Pathology, Medical Faculty, University of Zagreb, Zagreb 10000, Croatia
| | - Marina Peklic
- Department of Pharmacology, Medical Faculty, University of Zagreb, Zagreb 10000, Croatia
- Department of Pathology, Medical Faculty, University of Zagreb, Zagreb 10000, Croatia
| | - Robert Klicek
- Department of Pharmacology, Medical Faculty, University of Zagreb, Zagreb 10000, Croatia
- Department of Pathology, Medical Faculty, University of Zagreb, Zagreb 10000, Croatia
| | - Alen Pajtak
- Department of Pharmacology, Medical Faculty, University of Zagreb, Zagreb 10000, Croatia
- Department of Pathology, Medical Faculty, University of Zagreb, Zagreb 10000, Croatia
| | - Enio Amic
- Department of Pharmacology, Medical Faculty, University of Zagreb, Zagreb 10000, Croatia
- Department of Pathology, Medical Faculty, University of Zagreb, Zagreb 10000, Croatia
| | - Tinka Vidovic
- Department of Pharmacology, Medical Faculty, University of Zagreb, Zagreb 10000, Croatia
- Department of Pathology, Medical Faculty, University of Zagreb, Zagreb 10000, Croatia
| | - Mislav Rakic
- Department of Pharmacology, Medical Faculty, University of Zagreb, Zagreb 10000, Croatia
- Department of Pathology, Medical Faculty, University of Zagreb, Zagreb 10000, Croatia
| | - Marija Milkovic Perisa
- Department of Pharmacology, Medical Faculty, University of Zagreb, Zagreb 10000, Croatia
- Department of Pathology, Medical Faculty, University of Zagreb, Zagreb 10000, Croatia
| | - Katarina Horvat Pavlov
- Department of Pharmacology, Medical Faculty, University of Zagreb, Zagreb 10000, Croatia
- Department of Pathology, Medical Faculty, University of Zagreb, Zagreb 10000, Croatia
| | - Antonio Kokot
- Department of Pharmacology, Medical Faculty, University of Zagreb, Zagreb 10000, Croatia
- Department of Pathology, Medical Faculty, University of Zagreb, Zagreb 10000, Croatia
| | - Ante Tvrdeic
- Department of Pharmacology, Medical Faculty, University of Zagreb, Zagreb 10000, Croatia
- Department of Pathology, Medical Faculty, University of Zagreb, Zagreb 10000, Croatia
| | - Alenka Boban Blagaic
- Department of Pharmacology, Medical Faculty, University of Zagreb, Zagreb 10000, Croatia
- Department of Pathology, Medical Faculty, University of Zagreb, Zagreb 10000, Croatia
| | - Mario Zovak
- Department of Pharmacology, Medical Faculty, University of Zagreb, Zagreb 10000, Croatia
- Department of Pathology, Medical Faculty, University of Zagreb, Zagreb 10000, Croatia
| | - Sven Seiwerth
- Department of Pharmacology, Medical Faculty, University of Zagreb, Zagreb 10000, Croatia
- Department of Pathology, Medical Faculty, University of Zagreb, Zagreb 10000, Croatia
| | - Predrag Sikiric
- Department of Pharmacology, Medical Faculty, University of Zagreb, Zagreb 10000, Croatia
- Department of Pathology, Medical Faculty, University of Zagreb, Zagreb 10000, Croatia
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15
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Vukojević J, Siroglavić M, Kašnik K, Kralj T, Stanćić D, Kokot A, Kolarić D, Drmić D, Sever AZ, Barišić I, Šuran J, Bojić D, Patrlj MH, Sjekavica I, Pavlov KH, Vidović T, Vlainić J, Stupnišek M, Seiwerth S, Sikirić P. Rat inferior caval vein (ICV) ligature and particular new insights with the stable gastric pentadecapeptide BPC 157. Vascul Pharmacol 2018; 106:54-66. [PMID: 29510201 DOI: 10.1016/j.vph.2018.02.010] [Citation(s) in RCA: 37] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2017] [Revised: 11/10/2017] [Accepted: 02/25/2018] [Indexed: 02/07/2023]
Abstract
UNLABELLED Rat inferior caval vein (ICV) ligation (up to the right ovarian vein (ROV)) commonly represents a recapitulation of Virchow: with ligation leading to vessel injury, stasis, thrombosis and hemodynamic changes. We revealed that BPC 157's therapy collectively attenuated or counteracted all these events and the full syndrome. METHODS We applied BPC 157 (10 μg, 10 ng/kg) as an early regimen or as a delayed therapy. Assessment includes gross assessment by microcamera; microscopy, venography, bleeding, blood pressure, ECG, thermography, MDA and NO-level in plasma and ICV, and gene expression. RESULTS Direct vein injury, thrombosis, thrombocytopenia, prolonged bleeding were all counteracted. Also, rapid presentation of collaterals and redistribution of otherwise trapped blood volume (bypassing through the left ovarian vein (LOV) and other veins), with venous hypertension, arterial hypotension and tachycardia counteraction were shown. BPC 157-rats presented raised plasma NO-values, but normal MDA-values; in ICV tissue reverted low NO-values and counteracted increased MDA-levels. Altered expression of EGR, NOS, SRF, VEGFR and KRAS in ICV, ROV and LOV revealed increased or decreased levels, while some genes continuously remained unchanged. CONCLUSION As a new insight, BPC 157 application largely attenuated or even completely eliminated all consequences of ICV ligation in rats.
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Affiliation(s)
- Jakša Vukojević
- Departments of Pharmacology, University of Zagreb, Zagreb, Croatia.
| | - Marko Siroglavić
- Departments of Pharmacology, University of Zagreb, Zagreb, Croatia
| | - Katarina Kašnik
- Departments of Pharmacology, University of Zagreb, Zagreb, Croatia
| | - Tamara Kralj
- Departments of Pharmacology, University of Zagreb, Zagreb, Croatia
| | - Duje Stanćić
- Departments of Pharmacology, University of Zagreb, Zagreb, Croatia
| | - Antonio Kokot
- Departments of Pharmacology, University of Zagreb, Zagreb, Croatia
| | - Darko Kolarić
- Rudjer Boskovic Institute, Department of Molecular Medicine, Zagreb, Croatia
| | - Domagoj Drmić
- Departments of Pharmacology, University of Zagreb, Zagreb, Croatia
| | - Anita Zenko Sever
- Pathology, School of Medicine, University of Zagreb, Zagreb, Croatia
| | - Ivan Barišić
- Departments of Pharmacology, University of Zagreb, Zagreb, Croatia
| | - Jelena Šuran
- Departments of Pharmacology, University of Zagreb, Zagreb, Croatia
| | - Davor Bojić
- Departments of Pharmacology, University of Zagreb, Zagreb, Croatia
| | | | - Ivica Sjekavica
- Departments of Pharmacology, University of Zagreb, Zagreb, Croatia
| | | | - Tinka Vidović
- Departments of Pharmacology, University of Zagreb, Zagreb, Croatia
| | - Josipa Vlainić
- Rudjer Boskovic Institute, Department of Molecular Medicine, Zagreb, Croatia
| | | | - Sven Seiwerth
- Pathology, School of Medicine, University of Zagreb, Zagreb, Croatia
| | - Predrag Sikirić
- Departments of Pharmacology, University of Zagreb, Zagreb, Croatia
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Duzel A, Vlainic J, Antunovic M, Malekinusic D, Vrdoljak B, Samara M, Gojkovic S, Krezic I, Vidovic T, Bilic Z, Knezevic M, Sever M, Lojo N, Kokot A, Kolovrat M, Drmic D, Vukojevic J, Kralj T, Kasnik K, Siroglavic M, Seiwerth S, Sikiric P. Stable gastric pentadecapeptide BPC 157 in the treatment of colitis and ischemia and reperfusion in rats: New insights. World J Gastroenterol 2017; 23:8465-8488. [PMID: 29358856 PMCID: PMC5752708 DOI: 10.3748/wjg.v23.i48.8465] [Citation(s) in RCA: 46] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/02/2017] [Revised: 10/31/2017] [Accepted: 11/28/2017] [Indexed: 02/06/2023] Open
Abstract
AIM To provide new insights in treatment of colitis and ischemia and reperfusion in rats using stable gastric pentadecapeptide BPC 157. METHODS Medication [BPC 157, L-NAME, L-arginine (alone/combined), saline] was bath at the blood deprived colon segment. During reperfusion, medication was BPC 157 or saline. We recorded (USB microscope camera) vessel presentation through next 15 min of ischemic colitis (IC-rats) or reperfusion (removed ligations) (IC + RL-rats); oxidative stress as MDA (increased (IC- and IC + RL-rats)) and NO levels (decreased (IC-rats); increased (IC + RL-rats)) in colon tissue. IC + OB-rats [IC-rats had additional colon obstruction (OB)] for 3 d (IC + OB-rats), then received BPC 157 bath. RESULTS Commonly, in colon segment (25 mm, 2 ligations on left colic artery and vein, 3 arcade vessels within ligated segment), in IC-, IC + RL-, IC + OB-rats, BPC 157 (10 μg/kg) bath (1 mL/rat) increased vessel presentation, inside/outside arcade interconnections quickly reappeared, mucosal folds were preserved and the pale areas were small and markedly reduced. BPC 157 counteracted worsening effects induced by L-NAME (5 mg) and L-arginine (100 mg). MDA- and NO-levels were normal in BPC 157 treated IC-rats and IC + RL-rats. In addition, on day 10, BPC 157-treated IC + OB-rats presented almost completely spared mucosa with very small pale areas and no gross mucosal defects; the treated colon segment was of normal diameter, and only small adhesions were present. CONCLUSION BPC 157 is a fundamental treatment that quickly restores blood supply to the ischemically injured area and rapidly activates collaterals. This effect involves the NO system.
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Affiliation(s)
- Antonija Duzel
- Departments of Pharmacology and Pathology, Medical Faculty University of Zagreb, Zagreb 10000, Croatia
- Medical Faculty J.J. Strossmayer University of Osijek, Osijek, Croatia; Rudjer Boskovic Institute, Department of Molecular Medicine, Zagreb 10000, Croatia
| | - Josipa Vlainic
- Departments of Pharmacology and Pathology, Medical Faculty University of Zagreb, Zagreb 10000, Croatia
- Medical Faculty J.J. Strossmayer University of Osijek, Osijek, Croatia; Rudjer Boskovic Institute, Department of Molecular Medicine, Zagreb 10000, Croatia
| | - Marko Antunovic
- Departments of Pharmacology and Pathology, Medical Faculty University of Zagreb, Zagreb 10000, Croatia
- Medical Faculty J.J. Strossmayer University of Osijek, Osijek, Croatia; Rudjer Boskovic Institute, Department of Molecular Medicine, Zagreb 10000, Croatia
| | - Dominik Malekinusic
- Departments of Pharmacology and Pathology, Medical Faculty University of Zagreb, Zagreb 10000, Croatia
- Medical Faculty J.J. Strossmayer University of Osijek, Osijek, Croatia; Rudjer Boskovic Institute, Department of Molecular Medicine, Zagreb 10000, Croatia
| | - Borna Vrdoljak
- Departments of Pharmacology and Pathology, Medical Faculty University of Zagreb, Zagreb 10000, Croatia
- Medical Faculty J.J. Strossmayer University of Osijek, Osijek, Croatia; Rudjer Boskovic Institute, Department of Molecular Medicine, Zagreb 10000, Croatia
| | - Mariam Samara
- Departments of Pharmacology and Pathology, Medical Faculty University of Zagreb, Zagreb 10000, Croatia
- Medical Faculty J.J. Strossmayer University of Osijek, Osijek, Croatia; Rudjer Boskovic Institute, Department of Molecular Medicine, Zagreb 10000, Croatia
| | - Slaven Gojkovic
- Departments of Pharmacology and Pathology, Medical Faculty University of Zagreb, Zagreb 10000, Croatia
- Medical Faculty J.J. Strossmayer University of Osijek, Osijek, Croatia; Rudjer Boskovic Institute, Department of Molecular Medicine, Zagreb 10000, Croatia
| | - Ivan Krezic
- Departments of Pharmacology and Pathology, Medical Faculty University of Zagreb, Zagreb 10000, Croatia
- Medical Faculty J.J. Strossmayer University of Osijek, Osijek, Croatia; Rudjer Boskovic Institute, Department of Molecular Medicine, Zagreb 10000, Croatia
| | - Tinka Vidovic
- Departments of Pharmacology and Pathology, Medical Faculty University of Zagreb, Zagreb 10000, Croatia
- Medical Faculty J.J. Strossmayer University of Osijek, Osijek, Croatia; Rudjer Boskovic Institute, Department of Molecular Medicine, Zagreb 10000, Croatia
| | - Zdenko Bilic
- Departments of Pharmacology and Pathology, Medical Faculty University of Zagreb, Zagreb 10000, Croatia
- Medical Faculty J.J. Strossmayer University of Osijek, Osijek, Croatia; Rudjer Boskovic Institute, Department of Molecular Medicine, Zagreb 10000, Croatia
| | - Mario Knezevic
- Departments of Pharmacology and Pathology, Medical Faculty University of Zagreb, Zagreb 10000, Croatia
- Medical Faculty J.J. Strossmayer University of Osijek, Osijek, Croatia; Rudjer Boskovic Institute, Department of Molecular Medicine, Zagreb 10000, Croatia
| | - Marko Sever
- Departments of Pharmacology and Pathology, Medical Faculty University of Zagreb, Zagreb 10000, Croatia
- Medical Faculty J.J. Strossmayer University of Osijek, Osijek, Croatia; Rudjer Boskovic Institute, Department of Molecular Medicine, Zagreb 10000, Croatia
| | - Nermin Lojo
- Departments of Pharmacology and Pathology, Medical Faculty University of Zagreb, Zagreb 10000, Croatia
- Medical Faculty J.J. Strossmayer University of Osijek, Osijek, Croatia; Rudjer Boskovic Institute, Department of Molecular Medicine, Zagreb 10000, Croatia
| | - Antonio Kokot
- Departments of Pharmacology and Pathology, Medical Faculty University of Zagreb, Zagreb 10000, Croatia
- Medical Faculty J.J. Strossmayer University of Osijek, Osijek, Croatia; Rudjer Boskovic Institute, Department of Molecular Medicine, Zagreb 10000, Croatia
| | - Marijan Kolovrat
- Departments of Pharmacology and Pathology, Medical Faculty University of Zagreb, Zagreb 10000, Croatia
- Medical Faculty J.J. Strossmayer University of Osijek, Osijek, Croatia; Rudjer Boskovic Institute, Department of Molecular Medicine, Zagreb 10000, Croatia
| | - Domagoj Drmic
- Departments of Pharmacology and Pathology, Medical Faculty University of Zagreb, Zagreb 10000, Croatia
- Medical Faculty J.J. Strossmayer University of Osijek, Osijek, Croatia; Rudjer Boskovic Institute, Department of Molecular Medicine, Zagreb 10000, Croatia
| | - Jaksa Vukojevic
- Departments of Pharmacology and Pathology, Medical Faculty University of Zagreb, Zagreb 10000, Croatia
- Medical Faculty J.J. Strossmayer University of Osijek, Osijek, Croatia; Rudjer Boskovic Institute, Department of Molecular Medicine, Zagreb 10000, Croatia
| | - Tamara Kralj
- Departments of Pharmacology and Pathology, Medical Faculty University of Zagreb, Zagreb 10000, Croatia
- Medical Faculty J.J. Strossmayer University of Osijek, Osijek, Croatia; Rudjer Boskovic Institute, Department of Molecular Medicine, Zagreb 10000, Croatia
| | - Katarina Kasnik
- Departments of Pharmacology and Pathology, Medical Faculty University of Zagreb, Zagreb 10000, Croatia
- Medical Faculty J.J. Strossmayer University of Osijek, Osijek, Croatia; Rudjer Boskovic Institute, Department of Molecular Medicine, Zagreb 10000, Croatia
| | - Marko Siroglavic
- Departments of Pharmacology and Pathology, Medical Faculty University of Zagreb, Zagreb 10000, Croatia
- Medical Faculty J.J. Strossmayer University of Osijek, Osijek, Croatia; Rudjer Boskovic Institute, Department of Molecular Medicine, Zagreb 10000, Croatia
| | - Sven Seiwerth
- Departments of Pharmacology and Pathology, Medical Faculty University of Zagreb, Zagreb 10000, Croatia
- Medical Faculty J.J. Strossmayer University of Osijek, Osijek, Croatia; Rudjer Boskovic Institute, Department of Molecular Medicine, Zagreb 10000, Croatia
| | - Predrag Sikiric
- Departments of Pharmacology and Pathology, Medical Faculty University of Zagreb, Zagreb 10000, Croatia
- Medical Faculty J.J. Strossmayer University of Osijek, Osijek, Croatia; Rudjer Boskovic Institute, Department of Molecular Medicine, Zagreb 10000, Croatia
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Luetic K, Sucic M, Vlainic J, Halle ZB, Strinic D, Vidovic T, Luetic F, Marusic M, Gulic S, Pavelic TT, Kokot A, Seiwerth RS, Drmic D, Batelja L, Seiwerth S, Sikiric P. 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] [MESH Headings] [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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Affiliation(s)
- Krešimir Luetic
- Departments of Pharmacology and Pathology, School of Medicine, University of Zagreb, Salata 11, P.O. Box 916, 10000, Zagreb, Croatia
- Faculty of Medicine, J.J. Strossmayer University of Osijek, J. Huttlera 4, 31000, Osijek, Croatia
| | - Mario Sucic
- Departments of Pharmacology and Pathology, School of Medicine, University of Zagreb, Salata 11, P.O. Box 916, 10000, Zagreb, Croatia
- Faculty of Medicine, J.J. Strossmayer University of Osijek, J. Huttlera 4, 31000, Osijek, Croatia
| | - Josipa Vlainic
- Departments of Pharmacology and Pathology, School of Medicine, University of Zagreb, Salata 11, P.O. Box 916, 10000, Zagreb, Croatia
| | - Zeljka Belosic Halle
- Departments of Pharmacology and Pathology, School of Medicine, University of Zagreb, Salata 11, P.O. Box 916, 10000, Zagreb, Croatia
- Faculty of Medicine, J.J. Strossmayer University of Osijek, J. Huttlera 4, 31000, Osijek, Croatia
| | - Dean Strinic
- Departments of Pharmacology and Pathology, School of Medicine, University of Zagreb, Salata 11, P.O. Box 916, 10000, Zagreb, Croatia
- Faculty of Medicine, J.J. Strossmayer University of Osijek, J. Huttlera 4, 31000, Osijek, Croatia
| | - Tinka Vidovic
- Departments of Pharmacology and Pathology, School of Medicine, University of Zagreb, Salata 11, P.O. Box 916, 10000, Zagreb, Croatia
| | - Franka Luetic
- Departments of Pharmacology and Pathology, School of Medicine, University of Zagreb, Salata 11, P.O. Box 916, 10000, Zagreb, Croatia
| | - Marinko Marusic
- Departments of Pharmacology and Pathology, School of Medicine, University of Zagreb, Salata 11, P.O. Box 916, 10000, Zagreb, Croatia
- Faculty of Medicine, J.J. Strossmayer University of Osijek, J. Huttlera 4, 31000, Osijek, Croatia
| | - Sasa Gulic
- Departments of Pharmacology and Pathology, School of Medicine, University of Zagreb, Salata 11, P.O. Box 916, 10000, Zagreb, Croatia
| | - Tatjana Turudic Pavelic
- Departments of Pharmacology and Pathology, School of Medicine, University of Zagreb, Salata 11, P.O. Box 916, 10000, Zagreb, Croatia
| | - Antonio Kokot
- Departments of Pharmacology and Pathology, School of Medicine, University of Zagreb, Salata 11, P.O. Box 916, 10000, Zagreb, Croatia
- Faculty of Medicine, J.J. Strossmayer University of Osijek, J. Huttlera 4, 31000, Osijek, Croatia
| | - Ranka Serventi Seiwerth
- Departments of Pharmacology and Pathology, School of Medicine, University of Zagreb, Salata 11, P.O. Box 916, 10000, Zagreb, Croatia
| | - Domagoj Drmic
- Departments of Pharmacology and Pathology, School of Medicine, University of Zagreb, Salata 11, P.O. Box 916, 10000, Zagreb, Croatia
| | - Lovorka Batelja
- Departments of Pharmacology and Pathology, School of Medicine, University of Zagreb, Salata 11, P.O. Box 916, 10000, Zagreb, Croatia
| | - Sven Seiwerth
- Departments of Pharmacology and Pathology, School of Medicine, University of Zagreb, Salata 11, P.O. Box 916, 10000, Zagreb, Croatia
| | - Predrag Sikiric
- Departments of Pharmacology and Pathology, School of Medicine, University of Zagreb, Salata 11, P.O. Box 916, 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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Thwala LN, Préat V, Csaba NS. Emerging delivery platforms for mucosal administration of biopharmaceuticals: a critical update on nasal, pulmonary and oral routes. Expert Opin Drug Deliv 2016; 14:23-36. [PMID: 27351299 DOI: 10.1080/17425247.2016.1206074] [Citation(s) in RCA: 58] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
Abstract
INTRODUCTION Protein and peptide-based drugs are preferred therapeutics due to their specificity but are mainly administered by injection. Alternative routes for peptide delivery are preferred because of their ease of administration and increased patient compliance. Areas covered: This review provides a critical overview of current strategies for non-invasive mucosal delivery routes of therapeutic proteins and peptides, with emphasis on their advantages and limitations. Selected new trends and interesting novel formulations in advanced preclinical and clinical development stages for the pulmonary, nasal and the oral route are discussed for the most relevant peptide and protein drugs in terms of their specific requirements and intended therapeutic applications. Expert opinion: Despite the low frequency of clinical breakthroughs with non-invasive routes, these remain an active research area not only due to their improved therapeutic potential, but also due to the attractive commercial outcomes they offer. Currently, a number of technologies are adopted, including combinations of penetration enhancers with protease inhibitors and/or nanotechnology-based products and a few candidates are anticipated to be approved in the near future.
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Affiliation(s)
- Lungile Nomcebo Thwala
- a Center for Research in Molecular Medicine and Chronic Diseases (CIMUS), Health Research Institute of Santiago de Compostela (IDIS), Department of Pharmacy and Pharmaceutical Technology, School of Pharmacy , University of Santiago de Compostela , Santiago de Compostela , Spain.,b Louvain Drug Research Institute, Advanced Drug Delivery and Biomaterials , Université Catholique de Louvain , Brussels , Belgium
| | - Veronique Préat
- b Louvain Drug Research Institute, Advanced Drug Delivery and Biomaterials , Université Catholique de Louvain , Brussels , Belgium
| | - Noémi Stefania Csaba
- a Center for Research in Molecular Medicine and Chronic Diseases (CIMUS), Health Research Institute of Santiago de Compostela (IDIS), Department of Pharmacy and Pharmaceutical Technology, School of Pharmacy , University of Santiago de Compostela , Santiago de Compostela , Spain
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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 2016; 14:857-865. [PMID: 27138887 PMCID: PMC5333585 DOI: 10.2174/1570159x13666160502153022] [Citation(s) in RCA: 42] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [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
- Department of Pharmacology and Pathology, Medical Faculty, University of Zagreb, Zagreb, Croatia
| | - Sven Seiwerth
- Department of Pharmacology and Pathology, Medical Faculty, University of Zagreb, Zagreb, Croatia
| | - Rudolf Rucman
- Department of Pharmacology and Pathology, Medical Faculty, University of Zagreb, Zagreb, Croatia
| | - Danijela Kolenc
- Department of Pharmacology and Pathology, Medical Faculty, University of Zagreb, Zagreb, Croatia
| | - Lovorka Batelja Vuletic
- Department of Pharmacology and Pathology, Medical Faculty, University of Zagreb, Zagreb, Croatia
| | - Domagoj Drmic
- Department of Pharmacology and Pathology, Medical Faculty, University of Zagreb, Zagreb, Croatia
| | - Tihomir Grgic
- Department of Pharmacology and Pathology, Medical Faculty, University of Zagreb, Zagreb, Croatia
| | - Sanja Strbe
- Department of Pharmacology and Pathology, Medical Faculty, University of Zagreb, Zagreb, Croatia
| | - Goran Zukanovic
- Department of Pharmacology and Pathology, Medical Faculty, University of Zagreb, Zagreb, Croatia
| | - Dalibor Crvenkovic
- Department of Pharmacology and Pathology, Medical Faculty, University of Zagreb, Zagreb, Croatia
| | - Goran Madzarac
- Department of Pharmacology and Pathology, Medical Faculty, University of Zagreb, Zagreb, Croatia
| | - Iva Rukavina
- Department of Pharmacology and Pathology, Medical Faculty, University of Zagreb, Zagreb, Croatia
| | - Mario Sucic
- Department of Pharmacology and Pathology, Medical Faculty, University of Zagreb, Zagreb, Croatia
| | - Marko Baric
- Department of Pharmacology and Pathology, Medical Faculty, University of Zagreb, Zagreb, Croatia
| | - Neven Starcevic
- Department of Pharmacology and Pathology, Medical Faculty, University of Zagreb, Zagreb, Croatia
| | - Zoran Krstonijevic
- Department of Pharmacology and Pathology, Medical Faculty, University of Zagreb, Zagreb, Croatia
| | - Martina Lovric Bencic
- Department of Pharmacology and Pathology, Medical Faculty, University of Zagreb, Zagreb, Croatia
| | - Igor Filipcic
- Department of Pharmacology and Pathology, Medical Faculty, University of Zagreb, Zagreb, Croatia
| | - Dinko Stancic Rokotov
- Department of Pharmacology and Pathology, Medical Faculty, University of Zagreb, Zagreb, Croatia
| | - Josipa Vlainic
- Department of Molecular Medicine, Rudjer Boskovic Institute, Zagreb, Croatia
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Zemba M, Cilic AZ, Balenovic I, Cilic M, Radic B, Suran J, Drmic D, Kokot A, Stambolija V, Murselovic T, Holjevac JK, Uzun S, Djuzel V, Vlainic J, Seiwerth S, Sikiric P. BPC 157 antagonized the general anaesthetic potency of thiopental and reduced prolongation of anaesthesia induced by L-NAME/thiopental combination. Inflammopharmacology 2015; 23:329-336. [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] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2015] [Accepted: 09/28/2015] [Indexed: 02/06/2023]
Abstract
AIM We hypothesized that certain effects of the general anaesthetic thiopental are dependent on NO-related mechanisms, which were consequently counteracted by stable gastric pentadecapeptide BPC 157. MAIN METHODS (1) All rats intraperitoneally received thiopental (20, 30, 40, and 50 mg/kg) while medication BPC 157 (10 μg/kg, 10 ng/kg, and 10 pg/kg) was given intraperitoneally at 5 min before thiopental. (2) To determine NO-related mechanisms, all rats received intraperitoneally thiopental 40 mg/kg while BPC 157 (10 μg/kg), L-NAME (10 mg/kg) and L-arginine (30 mg/kg) were applied alone and/or combined. BPC 157 was given at 25 min before thiopental while L-NAME, L-arginine, alone and/or combined, were applied at 20 min before thiopental. KEY FINDINGS (1) BPC 157 own effect on thiopental anaesthesia: BPC 157 (10 ng/kg and 10 μg/kg) caused a significant antagonism of general anaesthesia produced by thiopental with a parallel shift of the dose-response curve to the right. (2) L-NAME-L-arginine-BPC 157 interrelations: L-NAME: Thiopental-induced anaesthesia duration was tripled. L-arginine: Usual thiopental anaesthesia time was not influenced. Active only when given with L-NAME or BPC 157: potentiating effects of L-NAME were lessened, not abolished; shortening effect of BPC 157: abolished. BPC 157 and L-NAME: Potentiating effects of L-NAME were abolished. BPC 157 and L-NAME and L-arginine: BPC 157 +L-NAME +L-arginine rats exhibited values close to those in BPC 157 rats. SIGNIFICANCE Thiopental general anaesthesia is simultaneously manipulated in both ways with NO system activity modulation, L-NAME (prolongation) and BPC 157 (shortening/counteraction) and L-arginine (interference with L-NAME and BPC 157).
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Affiliation(s)
- Mladen Zemba
- Department of Pharmacology, School of Medicine, University of Zagreb, Salata 11, PO Box 916, 10000, Zagreb, Croatia
| | - Andrea Zemba Cilic
- Department of Pharmacology, School of Medicine, University of Zagreb, Salata 11, PO Box 916, 10000, Zagreb, Croatia
| | - Igor Balenovic
- Department of Pharmacology, School of Medicine, University of Zagreb, Salata 11, PO Box 916, 10000, Zagreb, Croatia
| | - Matija Cilic
- Department of Pharmacology, School of Medicine, University of Zagreb, Salata 11, PO Box 916, 10000, Zagreb, Croatia
| | - Bozo Radic
- Department of Pharmacology, School of Medicine, University of Zagreb, Salata 11, PO Box 916, 10000, Zagreb, Croatia
| | - Jelena Suran
- Department of Pharmacology, School of Medicine, University of Zagreb, Salata 11, PO Box 916, 10000, Zagreb, Croatia
| | - Domagoj Drmic
- Department of Pharmacology, School of Medicine, University of Zagreb, Salata 11, PO Box 916, 10000, Zagreb, Croatia
| | - Antonio Kokot
- Department of Pharmacology, School of Medicine, University of Zagreb, Salata 11, PO Box 916, 10000, Zagreb, Croatia
| | - Vasilije Stambolija
- Department of Pharmacology, School of Medicine, University of Zagreb, Salata 11, PO Box 916, 10000, Zagreb, Croatia
| | - Tamara Murselovic
- Department of Pharmacology, School of Medicine, University of Zagreb, Salata 11, PO Box 916, 10000, Zagreb, Croatia
| | - Jadranka Katancic Holjevac
- Department of Pharmacology, School of Medicine, University of Zagreb, Salata 11, PO Box 916, 10000, Zagreb, Croatia
| | - Sandra Uzun
- Department of Pharmacology, School of Medicine, University of Zagreb, Salata 11, PO Box 916, 10000, Zagreb, Croatia
| | - Viktor Djuzel
- Department of Pharmacology, School of Medicine, University of Zagreb, Salata 11, PO Box 916, 10000, Zagreb, Croatia
| | - Josipa Vlainic
- Department of Pharmacology, School of Medicine, University of Zagreb, Salata 11, PO Box 916, 10000, Zagreb, Croatia
| | - Sven Seiwerth
- Department of Pathology, School of Medicine, University of Zagreb, Zagreb, Croatia
| | - Predrag Sikiric
- Department of Pharmacology, School of Medicine, University of Zagreb, Salata 11, PO Box 916, 10000, Zagreb, Croatia.
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Masnec S, Kokot A, Zlatar M, Kalauz M, Kunjko K, Radic B, Klicek R, Drmic D, Lazic R, Brcic L, Radic R, Ivekovic R, Seiwerth S, Sikiric P. Perforating corneal injury in rat and pentadecapeptide BPC 157. Exp Eye Res 2015; 136:9-15. [PMID: 25912999 DOI: 10.1016/j.exer.2015.04.016] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2014] [Revised: 04/09/2015] [Accepted: 04/22/2015] [Indexed: 12/12/2022]
Abstract
Based on its healing effects in various tissues, we hypothesized that the stable gastric pentadecapeptide BPC 157 heals corneal ulcerations in rats and effects corneal transparency. We made a penetrant linear 2-mm incision in the paralimbal region of the left cornea at the 5 o'clock position with a 20-gauge MVR incision knife at 45° under an operating microscope. Medication was BPC 157 (2 pg/mL, 2 ng/mL, and 2 μg/mL distilled water, two eye drops/left rat eye) immediately after injury induction and then every 8 h up to 120 h; controls received an equal volume of distilled water. In contrast to the poor healing response in controls, BPC 157 significantly accelerated the healing process in 2 μg and 2 ng BPC 157-treated eyes, starting 24 h after the injury, and the fluorescein and Seidel tests became negative. The epithelial defects were completely healed at 72 h (2 μg BPC 157-treated group) and at 96 h (2 ng BPC 157-treated group) after injury. Aqueous cells were absent at 96 h and 120 h after injury in the 2 μg and 2 ng BPC 157-treated groups, respectively. In conclusion, BPC 157 effects the rapid regaining of corneal transparency. Whereas controls developed new vessels that grew from the limbus to the penetrated area, BPC 157-treated rats generally had no new vessels, and those that did form in the limbus did not make contact with the penetrated area. Thus, BPC 157 eye drops successfully close perforating corneal incisions in rats.
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Affiliation(s)
- Sanja Masnec
- University Department of Ophthalmology, Zagreb University Hospital Center, Zagreb, Croatia
| | - Antonio Kokot
- Department of Anatomy and Neuroscience, School of Medicine, University of Osijek, Osijek, Croatia
| | - Mirna Zlatar
- Department of Pharmacology, School of Medicine, University of Zagreb, Zagreb, Croatia
| | - Miro Kalauz
- University Department of Ophthalmology, Zagreb University Hospital Center, Zagreb, Croatia
| | - Kristian Kunjko
- Department of Pharmacology, School of Medicine, University of Zagreb, Zagreb, Croatia
| | - Bozo Radic
- Department of Pharmacology, School of Medicine, University of Zagreb, Zagreb, Croatia
| | - Robert Klicek
- Department of Pharmacology, School of Medicine, University of Zagreb, Zagreb, Croatia
| | - Domagoj Drmic
- Department of Pharmacology, School of Medicine, University of Zagreb, Zagreb, Croatia
| | - Ratimir Lazic
- Department of Pharmacology, School of Medicine, University of Zagreb, Zagreb, Croatia
| | - Luka Brcic
- Department of Pathology, School of Medicine, University of Zagreb, Zagreb, Croatia
| | - Radivoje Radic
- Department of Anatomy and Neuroscience, School of Medicine, University of Osijek, Osijek, Croatia
| | - Renata Ivekovic
- University Department of Ophthalmology, Sestre Milosrdnice University Hospital Center, Zagreb, Croatia
| | - Sven Seiwerth
- Department of Pathology, School of Medicine, University of Zagreb, Zagreb, Croatia
| | - Predrag Sikiric
- Department of Pharmacology, School of Medicine, University of Zagreb, Zagreb, Croatia.
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Chang CH, Tsai WC, Hsu YH, Pang JHS. Pentadecapeptide BPC 157 enhances the growth hormone receptor expression in tendon fibroblasts. Molecules 2014; 19:19066-77. [PMID: 25415472 PMCID: PMC6271067 DOI: 10.3390/molecules191119066] [Citation(s) in RCA: 69] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2014] [Revised: 11/12/2014] [Accepted: 11/13/2014] [Indexed: 12/11/2022] Open
Abstract
BPC 157, a pentadecapeptide derived from human gastric juice, has been demonstrated to promote the healing of different tissues, including skin, muscle, bone, ligament and tendon in many animal studies. However, the underlying mechanism has not been fully clarified. The present study aimed to explore the effect of BPC 157 on tendon fibroblasts isolated from Achilles tendon of male Sprague-Dawley rat. From the result of cDNA microarray analysis, growth hormone receptor was revealed as one of the most abundantly up-regulated genes in tendon fibroblasts by BPC 157. BPC 157 dose- and time-dependently increased the expression of growth hormone receptor in tendon fibroblasts at both the mRNA and protein levels as measured by RT/real-time PCR and Western blot, respectively. The addition of growth hormone to BPC 157-treated tendon fibroblasts dose- and time-dependently increased the cell proliferation as determined by MTT assay and PCNA expression by RT/real-time PCR. Janus kinase 2, the downstream signal pathway of growth hormone receptor, was activated time-dependently by stimulating the BPC 157-treated tendon fibroblasts with growth hormone. In conclusion, the BPC 157-induced increase of growth hormone receptor in tendon fibroblasts may potentiate the proliferation-promoting effect of growth hormone and contribute to the healing of tendon.
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Affiliation(s)
- Chung-Hsun Chang
- Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, 259 Wen-Hwa 1st Road, Kwei-Shan, Tao-Yuan 333, Taiwan.
| | - Wen-Chung Tsai
- Department of Physical Medicine and Rehabilitation, Chang Gung Memorial Hospital, College of Medicine, Chang Gung University, Kwei-Shan, Tao-Yuan 333, Taiwan.
| | - Ya-Hui Hsu
- Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, 259 Wen-Hwa 1st Road, Kwei-Shan, Tao-Yuan 333, Taiwan.
| | - Jong-Hwei Su Pang
- Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, 259 Wen-Hwa 1st Road, Kwei-Shan, Tao-Yuan 333, Taiwan.
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Gamulin O, Serec K, Bilić V, Balarin M, Kosović M, Drmić D, Brčić L, Seiwerth S, Sikirić P. Monitoring the healing process of rat bones using Raman spectroscopy. J Mol Struct 2013; 1044:308-313. [DOI: 10.1016/j.molstruc.2013.01.049] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/27/2022]
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Cesarec V, Becejac T, Misic M, Djakovic Z, Olujic D, Drmic D, Brcic L, Rokotov DS, Seiwerth S, Sikiric P. Pentadecapeptide BPC 157 and the esophagocutaneous fistula healing therapy. Eur J Pharmacol 2013; 701:203-212. [PMID: 23220707 DOI: 10.1016/j.ejphar.2012.11.055] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2012] [Revised: 11/26/2012] [Accepted: 11/28/2012] [Indexed: 02/07/2023]
Abstract
Esophagocutaneous fistulas are a failure of the NO-system, due to NO-synthase blockage by the NOS-blocker L-NAME consequently counteracted by l-arginine and gastric pentadecapeptide BPC 157 (l-arginine
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Affiliation(s)
- Vedran Cesarec
- Department of Pharmacology, University of Zagreb, 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 2012; 129:652-659. [PMID: 21840572 DOI: 10.1016/j.thromres.2011.07.035] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [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; 667:322-329. [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; 88:535-542. [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] [MESH Headings] [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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Chang CH, Tsai WC, Lin MS, Hsu YH, Pang JHS. The promoting effect of pentadecapeptide BPC 157 on tendon healing involves tendon outgrowth, cell survival, and cell migration. J Appl Physiol (1985) 2010; 110:774-80. [PMID: 21030672 DOI: 10.1152/japplphysiol.00945.2010] [Citation(s) in RCA: 67] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023] Open
Abstract
Pentadecapeptide BPC 157, composed of 15 amino acids, is a partial sequence of body protection compound (BPC) that is discovered in and isolated from human gastric juice. Experimentally it has been demonstrated to accelerate the healing of many different wounds, including transected rat Achilles tendon. This study was designed to investigate the potential mechanism of BPC 157 to enhance healing of injured tendon. The outgrowth of tendon fibroblasts from tendon explants cultured with or without BPC 157 was examined. Results showed that BPC 157 significantly accelerated the outgrowth of tendon explants. Cell proliferation of cultured tendon fibroblasts derived from rat Achilles tendon was not directly affected by BPC 157 as evaluated by MTT assay. However, the survival of BPC 157-treated cells was significantly increased under the H(2)O(2) stress. BPC 157 markedly increased the in vitro migration of tendon fibroblasts in a dose-dependent manner as revealed by transwell filter migration assay. BPC 157 also dose dependently accelerated the spreading of tendon fibroblasts on culture dishes. The F-actin formation as detected by FITC-phalloidin staining was induced in BPC 157-treated fibroblasts. The protein expression and activation of FAK and paxillin were determined by Western blot analysis, and the phosphorylation levels of both FAK and paxillin were dose dependently increased by BPC 157 while the total amounts of protein was unaltered. In conclusion, BPC 157 promotes the ex vivo outgrowth of tendon fibroblasts from tendon explants, cell survival under stress, and the in vitro migration of tendon fibroblasts, which is likely mediated by the activation of the FAK-paxillin pathway.
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Affiliation(s)
- Chung-Hsun Chang
- Graduate Institute of Clinical Medical Sciences, Chang Gung Univ., 259 Wen-Hwa 1st Rd., Kwei-Shan, Tao-Yuan 333, Taiwan, Republic of China
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Cerovecki T, Bojanic I, Brcic L, Radic B, Vukoja I, Seiwerth S, Sikiric P. Pentadecapeptide BPC 157 (PL 14736) improves ligament healing in the rat. J Orthop Res 2010; 28:1155-1161. [PMID: 20225319 DOI: 10.1002/jor.21107] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/29/2009] [Accepted: 12/21/2009] [Indexed: 02/04/2023]
Abstract
We improved medial collateral ligament (MCL) healing throughout 90 days after surgical transection. We introduced intraperitoneal, per-oral (in drinking water) and topical (thin cream layer) peptide therapy always given alone, without a carrier. Previously, as an effective peptide therapy, stable gastric pentadecapeptide BPC 157 (GEPPPGKPADDAGLV, an anti-ulcer peptide effective in inflammatory bowel disease therapy (PL 14736)) particularly improved healing of transected tendon and muscle and wound healing effect including the expression of the early growth response 1 (egr-1) gene. After MCL transection BPC 157 was effective in rats when given once daily intraperitoneally (10 microg or 10 ng/kg) or locally as a thin layer (1.0 microg dissolved in distilled water/g commercial neutral cream) at the site of injury, first application 30 min after surgery and the final application 24 h before sacrifice. Likewise, BPC 157 was effective given per-orally (0.16 microg/ml in the drinking water (12 ml/day/rat)) until sacrifice. Commonly, BPC 157 microg-ng-rats exhibited consistent functional, biomechanical, macroscopic and histological healing improvements. Thus, we suggest BPC 157 improved healing of acute ligament injuries in further ligament therapy.
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Tudor M, Jandric I, Marovic A, Gjurasin M, Perovic D, Radic B, Blagaic AB, Kolenc D, Brcic L, Zarkovic K, Seiwerth S, Sikiric P. Traumatic brain injury in mice and pentadecapeptide BPC 157 effect. REGULATORY PEPTIDES 2010; 160:26-32. [PMID: 19931318 DOI: 10.1016/j.regpep.2009.11.012] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/25/2009] [Revised: 11/11/2009] [Accepted: 11/12/2009] [Indexed: 01/18/2023]
Abstract
Gastric pentadecapeptide BPC 157 (GEPPPGKPADDAGLV, an anti-ulcer peptide, efficient in inflammatory bowel disease trials (PL 14736), no toxicity reported, improved muscle crush injury. After an induced traumatic brain injury (TBI) in mice by a falling weight, BPC 157 regimens (10.0microg, 10.0ng/kgi.p.) demonstrated a marked attenuation of damage with an improved early outcome and a minimal postponed mortality throughout a 24h post-injury period. Ultimately, the traumatic lesions (subarachnoidal and intraventricular haemorrhage, brain laceration, haemorrhagic laceration) were less intense and consecutive brain edema had considerably improved. Given prophylactically (30 min before TBI) the improved conscious/unconscious/death ratio in TBI-mice was after force impulses of 0.068 Ns, 0.093 Ns, 0.113 Ns, 0.130 Ns, 0.145 Ns, and 0.159 Ns. Counteraction (with a reduction of unconsciousness, lower mortality) with both microg- and ng-regimens included the force impulses of 0.068-0.145 Ns. A higher regimen presented effectiveness also against the maximal force impulse (0.159 Ns). Furthermore, BPC 157 application immediately prior to injury was beneficial in mice subjected to force impulses of 0.093 Ns-TBI. For a more severe force impulse (0.130 Ns, 0.145 Ns, or 0159 Ns), the time-relation to improve the conscious/unconscious/death ratio was: 5 min (0.130 Ns-TBI), 20 min (0.145 Ns-TBI) or 30 min (0.159 Ns-TBI).
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Affiliation(s)
- Mario Tudor
- Department of Pharmacology, Medical Faculty University of Zagreb, 10000 Zagreb, Croatia
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Sever M, Klicek R, Radic B, Brcic L, Zoricic I, Drmic D, Ivica M, Barisic I, Ilic S, Berkopic L, Blagaic AB, Coric M, Kolenc D, Vrcic H, Anic T, Seiwerth S, Sikiric P. Gastric pentadecapeptide BPC 157 and short bowel syndrome in rats. Dig Dis Sci 2009; 54:2070-2083. [PMID: 19093208 DOI: 10.1007/s10620-008-0598-y] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/03/2008] [Accepted: 10/17/2008] [Indexed: 12/11/2022]
Abstract
The gastric pentadecapeptide BPC 157, which was shown to be safe as an antiulcer peptide in trials for inflammatory bowel disease (PL14736, Pliva), successfully healed intestinal anastomosis and fistula in rat. Therefore, we studied for 4 weeks rats with escalating short bowel syndrome and progressive weight loss after small bowel resection from fourth ileal artery cranially of ileocecal valve to 5 cm beneath pylorus. BPC 157 (10 microg/kg or 10 ng/kg) was given perorally, in drinking water (12 ml/rat/day) or intraperitoneally (once daily, first application 30 min following surgery, last 24 h before sacrifice). Postoperatively, features of increasingly exhausted presentation were: weight loss appearing immediately regardless of villus height, twofold increase in crypt depth and fourfold increase in muscle thickness within the first week, jejunal and ileal overdilation, and disturbed jejunum/ileum relation. In contrast, constant weight gain above preoperative values was observed immediately with BPC 157 therapy, both perorally and parenterally, and villus height, crypt depth, and muscle thickness [inner (circular) muscular layer] also increased, at 7, 14, 21, and 28 days. Moreover, rats treated with pentadecapeptide BPC 157 showed not different jejunal and ileal diameters, constant jejunum-to-ileum ratio, and increased anastomosis breaking strength. In conclusion, pentadecapeptide BPC 157 could be helpful to cure short bowel syndrome.
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Affiliation(s)
- Marko Sever
- Department of Pharmacology, Medical School, University of Zagreb, Salata 11, 10000, Zagreb, Croatia
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Balenovic D, Bencic ML, Udovicic M, Simonji K, Hanzevacki JS, Barisic I, Kranjcevic S, Prkacin I, Coric V, Brcic L, Coric M, Brcic I, Borovic S, Radic B, Drmic D, Vrcic H, Seiwerth S, Sikiric P. Inhibition of methyldigoxin-induced arrhythmias by pentadecapeptide BPC 157: a relation with NO-system. REGULATORY PEPTIDES 2009; 156:83-89. [PMID: 19465062 DOI: 10.1016/j.regpep.2009.05.008] [Citation(s) in RCA: 41] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/05/2009] [Revised: 05/11/2009] [Accepted: 05/17/2009] [Indexed: 12/11/2022]
Abstract
Pentadecapeptide BPC 157 (GEPPPGKPADDAGLV, MW 1419) reversed congestive heart failure and various arrhythmias, influenced the NO-system and showed no proarrhythmic effect. In therapy analogy, we challenged rats with digitalis, to show attenuation by BPC 157 and the relation between the NO-system and digitalis toxicity. (i). BPC 157 prophylactic effect. Development of cumulative intravenous digitalis toxicity, BPC 157 (50 microg, 10 microg, 10 ng/kg applied intravenously immediately before a methyldigoxin increment regimen (2.0/1.5/1.5/1.0 mg/kg at 15 min-intervals, total dose 6.0 mg/kg/45 min)) reduced the number of ventricular premature beats, prolonged the time before onset of ventricular tachycardia, reduced ventricular tachycardia and AV-block duration (microg-regimes) or reduced mainly the AV-block duration (ng-regimen). (ii). BPC 157 therapy. Advanced methyldigoxin toxicity (6.0 mg/kg i.v. bolus). BPC 157 applied at the 20th second of the grade 3 AV-block shortened AV-blocks, mitigated a further digitalis toxicity course. Ventricular tachycardias were either avoided (50 microg), or markedly reduced (10 microg, 10 ng). Fatal outcome was either avoided (50 microg), reduced (10 microg), or only delayed (10 ng) (iii) BPC 157, L-NAME, l-arginine, L-NAME+l-arginine application. L-NAME-application (5 mg/kg i.p.) aggravated methyldigoxin-arrhythmias. l-arginine (200 mg/kg i.p.) alone had no effect but blunted L-NAME-exaggeration (L-NAME+l-arginine). In this respect, BPC 157 (50 microg/kg i.p.) was prophylactically and therapeutically more effective: the antagonism of L-NAME with BPC 157 produced an effect similar to BPC 157 alone. In conclusion, digitalis-induced arrhythmias in rats could be prevented and counteracted by pentadecapeptide BPC 157, mainly through an interaction with the NO-system.
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Affiliation(s)
- Dijana Balenovic
- Department of Pharmacology, University of Zagreb Medical School, Salata 11, 10000 Zagreb, Croatia
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Skorjanec S, Dolovski Z, Kocman I, Brcic L, Blagaic Boban A, Batelja L, Coric M, Sever M, Klicek R, Berkopic L, Radic B, Drmic D, Kolenc D, Ilic S, Cesarec V, Tonkic A, Zoricic I, Mise S, Staresinic M, Ivica M, Lovric Bencic M, Anic T, Seiwerth S, Sikiric P. Therapy for unhealed gastrocutaneous fistulas in rats as a model for analogous healing of persistent skin wounds and persistent gastric ulcers: stable gastric pentadecapeptide BPC 157, atropine, ranitidine, and omeprazole. Dig Dis Sci 2009; 54:46-56. [PMID: 18649140 DOI: 10.1007/s10620-008-0332-9] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/07/2008] [Accepted: 05/06/2008] [Indexed: 12/18/2022]
Abstract
OBJECTIVE This study focused on unhealed gastrocutaneous fistulas to resolve whether standard drugs that promote healing of gastric ulcers may simultaneously have the same effect on cutaneous wounds, and corticosteroid aggravation, and to demonstrate why peptides such as BPC 157 exhibit a greater healing effect. Therefore, with the fistulas therapy, we challenge the wound/growth factors theory of the analogous nonhealing of wounds and persistent gastric ulcers. METHODS The healing rate of gastrocutaneous fistula in rat (2-mm-diameter stomach defect, 3-mm-diameter skin defect) validates macro/microscopically and biomechanically a direct skin wound/stomach ulcer relation, and identifies a potential therapy consisting of: (i) stable gastric pentadecapeptide BPC 157 [in drinking water (10 microg/kg) (12 ml/rat/day) or intraperitoneally (10 microg/kg, 10 ng/kg, 10 pg/kg)], (ii) atropine (10 mg/kg), ranitidine (50 mg/kg), and omeprazole (50 mg/kg), (iii) 6-alpha-methylprednisolone (1 mg/kg) [intraperitoneally, once daily, first application at 30 min following surgery; last 24 h before sacrifice (at postoperative days 1, 2, 3, 7, 14, and 21)]. RESULTS Greater anti-ulcer potential and efficiency in wound healing compared with standard agents favor BPC 157, efficient in inflammatory bowel disease (PL-14736, Pliva), given in drinking water or intraperitoneally. Even after 6-alpha-methylprednisolone aggravation, BPC 157 promptly improves both skin and stomach mucosa healing, and closure of fistulas, with no leakage after up to 20 ml water intragastrically. Standard anti-ulcer agents, after a delay, improve firstly skin healing and then stomach mucosal healing, but not fistula leaking and bursting strength (except for atropine). CONCLUSION We conclude that BPC 157 may resolve analogous nonhealing of wounds and persistent gastric ulcers better than standard agents.
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Affiliation(s)
- Sandra Skorjanec
- Department of Pharmacology, Medical School, University of Zagreb, Salata 11, 10000, 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; 38:716-725. [PMID: 18668315 DOI: 10.1007/s00595-007-3706-2] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [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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Dobric I, Drvis P, Petrovic I, Shejbal D, Brcic L, Blagaic AB, Batelja L, Sever M, Kokic N, Tonkic A, Zoricic I, Mise S, Staresinic M, Radic B, Jakir A, Babel J, Ilic S, Vuksic T, Jelic I, Anic T, Seiwerth S, Sikiric P. Prolonged esophagitis after primary dysfunction of the pyloric sphincter in the rat and therapeutic potential of the gastric pentadecapeptide BPC 157. J Pharmacol Sci 2007; 104:7-18. [PMID: 17452811 DOI: 10.1254/jphs.fp0061322] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
Seven or fourteen days or twelve months after suturing one tube into the pyloric sphincter (removed by peristalsis by the seventh day), rats exhibit prolonged esophagitis with a constantly lowered pressure not only in the pyloric, but also in the lower esophageal sphincter and a failure of both sphincters. Throughout the esophagitis experiment, gastric pentadecapeptide BPC 157 (PL 14736) is given intraperitoneally once a day (10 microg/kg, 10 ng/kg, last application 24 h before assessment), or continuously in drinking water at 0.16 microg/ml, 0.16 ng/ml (12 ml/rat per day), or directly into the stomach 5 min before pressure assessment (a water manometer connected to the drainage port of a Foley catheter implanted into the stomach either through an esophageal or duodenal incision). This treatment alleviates i) the esophagitis (macroscopically and microscopically, at either region or interval), ii) the pressure in the pyloric sphincter, and iii) the pressure in the lower esophageal sphincter (cmH2O). In the normal rats it increases lower esophageal sphincter pressure, but decreases the pyloric sphincter pressure. Ranitidine, given using the same protocol (50 mg/kg, intraperitoneally, once daily; 0.83 mg/ml in drinking water; 50 mg/kg directly into the stomach) does not have an effect in either rats with esophagitis or in normal rats.
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Affiliation(s)
- Ivan Dobric
- Department of Pharmacology, Medical School, University of Zagreb, Croatia
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