Novel synthetic benzimidazole-derived oligosaccharide, M3BIM, prevents ex vivo platelet aggregation and in vivo thromboembolism

Ting Lin Yen, Ming Ping Wu, Chi Li Chung, Wen Bin Yang, Thanasekaran Jayakumar, Pitchairaj Geraldine, Chih Ming Chou, Chia Yau Chang, Wan-Jung Lu, Joen Rong Sheu

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

Background: Thrombus formation, a phenomenon primarily related to increased platelet activation, plays a key role in cardiovascular and cerebrovascular diseases. Although the established antiplatelet agents, such as aspirin and clopidogrel, have been shown to be beneficial in treating thromboembolic diseases, they have considerable limitations. Hence, the development of more effective and safe antithrombotic agents is necessary to satisfy a substantial unmet clinical need. In recent years, the favorable properties of imidazole-related drugs have prompted medicinal chemists to synthesize numerous novel therapeutic agents. The chemical structure of the benzimidazole backbone has proven antiplatelet properties. Moreover, synthetic oligosaccharides have exhibited antiplatelet properties. Therefore, we developed a new aldo-benzimidazole-derived oligosaccharide compound, M3BIM, for achieving a stronger antiplatelet effect than the drugs which are being used in clinical aspects. We investigated the effects of M3BIM on platelet activation ex vivo and its antithrombotic activity in vivo. Results: M3BIM (10-50 μM) exhibited a more potent activity in inhibiting platelet aggregation stimulated by collagen than it did in inhibiting that stimulated by thrombin in washed human platelets. The M3BIM treatment revealed no cytotoxicity in zebrafish embryos, even at the highest concentration of 100 μM. In addition, M3BIM inhibited the phosphorylation of phospholipase Cγ2, protein kinase C (PKC), and mitogen-activated protein kinases (MAPKs; extracellular signal-regulated kinase 2 and c-Jun N-terminal kinase 1), and markedly reduced the ATP-release reaction and intracellular calcium mobilization in collagen-activated platelets. By contrast, M3BIM showed no effects on either collagen-induced p38 MAPK and Akt phosphorylation or phorbol 12, 13-dibutyrate-induced PKC activation and platelet aggregation. Moreover, the M3BIM treatment substantially prolonged the closure time in human whole blood, and increased the occlusion time in mesenteric microvessels and attenuated cerebral infarction in mice. For the study of anticoagulant activities, M3BIM showed no significant effects in the prolongation of activated partial thromboplastin time and prothrombin time in mice. Conclusion: The findings of our study suggest that M3BIM is a potential therapeutic agent for preventing or treating thromboembolic disorders.

Original languageEnglish
Article number26
JournalJournal of Biomedical Science
Volume23
Issue number1
DOIs
Publication statusPublished - Feb 17 2016

Keywords

  • Arterial thrombosis
  • Benzimidazole-derived oligosaccharide
  • Cerebral infarction
  • Platelet aggregation

ASJC Scopus subject areas

  • Clinical Biochemistry
  • Molecular Biology
  • Cell Biology
  • Biochemistry, medical
  • Endocrinology, Diabetes and Metabolism
  • Pharmacology (medical)

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