Background: Thrombus formation, a phenomenon primarily related to increased platelet activation, plays a key role\nin cardiovascular and cerebrovascular diseases. Although the established antiplatelet agents, such as aspirin and\nclopidogrel, have been shown to be beneficial in treating thromboembolic diseases, they have considerable\nlimitations. Hence, the development of more effective and safe antithrombotic agents is necessary to satisfy a\nsubstantial unmet clinical need. In recent years, the favorable properties of imidazole-related drugs have prompted\nmedicinal chemists to synthesize numerous novel therapeutic agents. The chemical structure of the benzimidazole\nbackbone has proven antiplatelet properties. Moreover, synthetic oligosaccharides have exhibited antiplatelet\nproperties. Therefore, we developed a new aldo-benzimidazole-derived oligosaccharide compound, M3BIM, for\nachieving a stronger antiplatelet effect than the drugs which are being used in clinical aspects. We investigated\nthe effects of M3BIM on platelet activation ex vivo and its antithrombotic activity in vivo.\nResults: M3BIM (10ââ?¬â??50 Ã?¼M) exhibited a more potent activity in inhibiting platelet aggregation stimulated by\ncollagen than it did in inhibiting that stimulated by thrombin in washed human platelets. The M3BIM treatment\nrevealed no cytotoxicity in zebrafish embryos, even at the highest concentration of 100 Ã?¼M. In addition, M3BIM\ninhibited the phosphorylation of phospholipase CÃ?³2, protein kinase C (PKC), and mitogen-activated protein kinases\n(MAPKs; extracellular signal-regulated kinase 2 and c-Jun N-terminal kinase 1), and markedly reduced the ATPrelease\nreaction and intracellular calcium mobilization in collagen-activated platelets. By contrast, M3BIM showed no\neffects on either collagen-induced p38 MAPK and Akt phosphorylation or phorbol 12, 13-dibutyrate-induced PKC\nactivation and platelet aggregation. Moreover, the M3BIM treatment substantially prolonged the closure time in\nhuman whole blood, and increased the occlusion time in mesenteric microvessels and attenuated cerebral\ninfarction in mice. For the study of anticoagulant activities, M3BIM showed no significant effects in the prolongation\nof activated partial thromboplastin time and prothrombin time in mice.\nConclusion: The findings of our study suggest that M3BIM is a potential therapeutic agent for preventing or\ntreating thromboembolic disorders.
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