Doxepin inhibits GPVI-dependent platelet Ca2+ signaling and collagen-dependent thrombus formation

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Antidepressant Doxepin impairs inositol signaling pathway in platelets

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Rupture of the atherosclerotic plaque exposes subendothelial collagen to the bloodstream. Platelets are activated upon contact with collagen, causing platelet adhesion, secretion of platelet contents, and platelet aggregation at the site of injury. A blood clot forms, leading to development of thrombosis accompanied by a high risk of acute vessel occlusion.
Doxepin is well-known tricyclic antidepressant commonly used to treat symptoms of depression and/or anxiety associated with alcoholism, psychiatric problems, and manic-depressive conditions. Many side effects have been reported about this molecule but, unexpectedly, Doxepin can have a positive cardioprotective effect on thrombus formation because it impairs platelet activation.
How can this be possible? And how is it explained at the biological level? Sascha Geue provides the answer in this study.
To summarize, Doxepin acts as an antagonist of Collagen-Related Peptide (CRP) binding on collagen receptor glycoprotein VI (GPVI). CRP binding triggers the activation of PLC2; generation of second messengers IP3 and DAG; and ultimately increases Ca2+ concentration in the platelets that trigger their activation.
The Inositol Phosphate cascade is at the top of the cascade of events that lead to Ca2+ flux. Because IP3 is not stable and is rapidly degraded first into IP2, then IP1, Sasha used in-vitro quantification of IP1 to decipher the mechanism of action of Doxepin on platelets isolated from mouse blood.
Pharmacology is truly amazing! Would you have ever imagined that an antidepressant could potentially prevent platelet activation, thrombus formation, and could thus have a protective vascular effect?
Granted, among Doxepin’s numerous mechanisms of action, its role in Inositol Phosphate production and its impact on platelet aggregation was not immediately evident


Platelet adhesion, activation, and aggregation are essential for primary hemostasis, but are also critically involved in the development of acute arterial thrombotic occlusion. Stimulation of the collagen receptor glycoprotein VI (GPVI) leads to phospholipase Cγ2-dependent inositol triphosphate (IP3) production with subsequent platelet activation, due to increased intracellular Ca2+ concentration ([Ca2+]i). Although tricyclic antidepressants have been shown to potentially impair platelet activation, nothing is hitherto known about potential effects of the tricyclic antidepressant doxepin on platelet Ca2+ signaling and thrombus formation. As shown in the present study, doxepin significantly diminished the stimulatory effect of GPVI agonist collagen-related peptide (CRP) on intracellular Ca2+ release as well as subsequent extracellular Ca2+ influx. Doxepin was partially effective by impairment of CRP-dependent IP3 production. Moreover, doxepin abrogated CRP-induced platelet degranulation and integrin αIIbβ3 activation and aggregation. Finally, doxepin markedly blunted in vitro platelet adhesion to collagen and thrombus formation under high arterial shear rates (1,700-s). In conclusion, doxepin is a powerful inhibitor of GPVI-dependent platelet Ca2+ signaling, platelet activation, and thrombus formation.T


Am. J. Physiol. Cell. Physiol. 2017 Jun 1;312(6):C765-C774.

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