PB0365 - A novel and potent collagen antagonist, Niclosamide in human platelets: in vitro and in vivo studies.

Background: Numerous cardiovascular disorders are caused by intravascular thrombosis. When a blood artery is injured, platelets cling to the disturbed surface and release a number of physiologically active substances that cause aggregation. Platelet activation is relevant in a variety of cardiovascular and cerebrovascular disorders. Recent studies indicated that Signal Transducer and Activator of Transcription 3 (STAT3) inhibitors selectively inhibited collagen-induced aggregation of human platelets. Niclosamide is an oral anthelmintic medication used to treat parasitic infections in millions of people worldwide and is a STAT3 inhibitor modulating signaling pathways.

Aims: To investigate the molecular mechanism of Niclosamide inhibits collagen-induced platelet aggregation.

Methods: Platelet aggregation, ATP-release, and thromboxane A2 were used to assess the anti-platelet activity of Niclosamide. FeCl3-induced platelet thrombi in mesenteric microvessels of mice and tail bleeding time were used for an in vivo study.

Results: Our results showed that Niclosamide inhibited platelet aggregation and the ATP-release reaction in washed human platelets stimulated by collagen, but not by thrombin, arachidonic acid, ADP, or U46619. Niclosamide produced a concentration-related rightward displacement of the collagen concentration-response curve indicating specific antagonism. Niclosamide inhibits platelet aggregation at least by suppressing the synthesis of thromboxane A2. Western blot analysis showed that treatment with collagen produced PLCγ2 and Syk phosphorylation. We noted that Niclosamide inhibited collagen-induced PLCγ2 and Syk phosphorylation. Moreover, treatment with Niclosamide significantly prolonged the tail bleeding time and increased the latency of occlusion time in FeCl3-induced platelet plug formation in mesenteric venules of mice.

Conclusion(s): Our study indicated that Niclosamide suppresses platelet aggregation specifically inhibits collagen-induced platelet activation and inhibits the production of thromboxane A2. Thus, Niclosamide treatment may represent a novel approach to lowering the risk of or improving function in thromboembolism-related disorders.
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