While cardiovascular disease (CVD) is the leading cause of death, major depressive disorder (MDD) is the primary cause of disability, affecting more than 300 million people worldwide. Interestingly, there is evidence that CVD is more prevalent in people with MDD. It is well established that neurotransmitters, namely serotonin and norepinephrine, are involved in the biochemical mechanisms of MDD, and consequently, drugs targeting serotonin-norepinephrine reuptake, such as duloxetine, are commonly prescribed for MDD. In this connection, serotonin and norepinephrine are also known to play critical roles in primary hemostasis. Based on these considerations, we investigated if duloxetine can be repurposed as an antiplatelet medication. Our results-using human and/or mouse platelets show that duloxetine dose-dependently inhibited agonist-induced platelet aggregation, compared to the vehicle control. Furthermore, it also blocked agonist-induced dense and α-granule secretion, integrin αIIbβ3 activation, phosphatidylserine expression, and clot retraction. Moreover duloxetine-treated mice had a significantly prolonged occlusion time. Finally, duloxetine was also found to impair hemostasis. Collectively, our data indicate that the antidepressant duloxetine, which is a serotonin-norepinephrine antagonist, exerts antiplatelet and thromboprotective effects and inhibits hemostasis. Consequently, duloxetine, or a rationally designed derivative, presents potential benefits in the context of CVD, including that associated with MDD.
Cardiovascular disease (CVD) is the leading cause of death. Patients with major depressive disorder (MDD) are at higher risk of developing CVD. It has been shown that serotonin plays a key role in the biochemical mechanisms of MDD as well in primary hemostasis mediated by potentiation platelet activity. Consequently, drugs targeting serotonin reuptake such as the FDA‐approved duloxetine are commonly prescribed for MDD. Since platelets also express the serotonin transporter (SERT) and serotonin is known to enhance platelet aggregation, this drug can potentially be repurposed as an antiplatelet medication and could be useful in MDD patients who have a higher risk of developing CVD. Based on these considerations, we investigated the antiplatelet activity of duloxetine by employing a host of in vitro and in vivo platelet assays using human blood and mouse model. Our results show that duloxetine has the capacity to dose‐dependently inhibit agonist‐induced platelet aggregation in vitro. Furthermore, agonist induced dense and α‐ granule secretion, αIIbβ3 integrin activation, phosphatidylserine expression, and clot retraction were inhibited in duloxetine treated platelets compared to those treated with vehicle control. Moreover, in the carotid artery injury thrombosis model, duloxetine‐treated mice had a significantly prolonged occlusion time in comparison with those treated with vehicle control. Collectively, our data indicate that the duloxetine exerts antiplatelet effects and protects against thrombosis. Consequently, duloxetine can serve as a potential antiplatelet drug in MDD patients who have a higher risk of developing CVD.
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