Drug Design, Development and Therapy (2020-12-01)

Clopidogrel-Induced Gastric Injury in Rats is Attenuated by Stable Gastric Pentadecapeptide BPC 157

  • Wu H,
  • Wei M,
  • Li N,
  • Lu Q,
  • Shrestha SM,
  • Tan J,
  • Zhang Z,
  • Wu G,
  • Shi R

Journal volume & issue
Vol. Volume 14
pp. 5599 – 5610

Abstract

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Hailu Wu,1,2 Ming Wei,2 Nan Li,2 Qin Lu,2 Sachin Mulmi Shrestha,1 Jiacheng Tan,2 Zhenyu Zhang,3 Guoqiu Wu,4,5 Ruihua Shi2 1Medical School of Southeast University, Nanjing 210009, People’s Republic of China; 2Department of Gastroenterology, Zhongda Hospital Affiliated to Southeast University, Nanjing 210009, People’s Republic of China; 3Division of Gastroenterology, Department of Medicine, Nanjing Medical University Nanjing First Hospital, Nanjing 210009, People’s Republic of China; 4Center of Clinical Laboratory Medicine, Zhongda Hospital, Southeast University, Nanjing 210009, People’s Republic of China; 5Jiangsu Provincial Key Laboratory of Critical Care Medicine, Nanjing 210009, People’s Republic of ChinaCorrespondence: Ruihua ShiDepartment of Gastroenterology, Zhongda Hospital Affiliated to Southeast University, Nanjing 210009, People’s Republic of ChinaTel +86 25 83262833Fax +86 25 83262830Email [email protected] WuCenter of Clinical Laboratory Medicine, Zhongda Hospital, Southeast University, Nanjing 210009, People’s Republic of ChinaTel +86-25 83272150Email [email protected]: Although Clopidogrel is safe in healthy volunteers, it can induce recurrence of gastric ulcers in high-risk patients. Here, we investigated the protective effect of the natural product, stable gastric pentadecapeptide 157 (BPC 157) on Clopidogrel-induced gastric injury.Methods: We used acetic acid to induce gastric ulcer in Sprague Dawley rats. Clopidogrel alone or in combination with BPC 157 or L-NAME (nitric oxide system blockade) were administered after healing of acetic acid-induced ulcer. One percent methylcellulose solution was used as control. Ulcer recurrence rate and the ulcer index were compared between these groups. Gastric mucosal apoptosis rate, microscopic inflammation activity and angiogenesis markers vascular endothelial growth factor A (VEGF-A) and CD34 were examined by TUNEL, histological evaluations (HE) and immunohistochemistry (IHC). Pathways involved, expressions of endoplasmic reticulum (ER) stress apoptosis marker CHOP, angiogenic markers VEGF-A and its receptor VEGFR1, and endothelial NO synthase (eNOS) were all analyzed by Western blot.Results: This study indicated that Clopidogrel significantly induced the gastric ulcers recurrence, severe inflammation and ER stress related apoptosis of the gastric mucosa, suppressed the synthesis of angiogenic markers and eNOS. Furthermore, Clopidrogel intervention resulted in the activation of protein kinase B (AKT) and p38 mitogen-activated protein kinase (p38/MAPK). BPC 157 attenuated the gastric mucosal damage caused by Clopidogrel and reversed these molecular effects. However, NO blockade L-NAME weakened the protective effect and thus the molecular effects of BPC 157 on gastric mucosa.Conclusion: In conclusion, these results suggest that BPC 157 inhibited Clopidogrel-induced gastric mucosa injury partially by inhibition of gastric mucosa cell ER stress-mediated apoptosis and inflammation, and promoting gastric mucosa angiogenesis via VEGF-A/VEGFR1 mediated-AKT/p38/MAPK signaling pathways.Keywords: clopidogrel, BPC 157, angiogenesis, AKT, p38/MAPK

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