Ginkgetin mitigates cerebral infarction by inhibiting platelet activation via the PLCγ2-dependent pathway in human subjects and mice

Platelet activation plays a crucial role in cerebral vascular diseases (CVDs) such as ischemic stroke, making the suppression of platelet function a promising strategy for mitigating CVDs. Ginkgetin (GK), from Ginkgo biloba L, known for its diverse bioactivities, remains largely unexplored in modulating platelet activity. This study systematically investigated GK's effects on human platelets, aiming to understand its therapeutic potential in alleviating CVDs. The experiments examined GK's effects on human platelets, analyzing aggregation, secretion, calcium mobilization, and thromboxane generation induced by agonists. GK potently inhibited and suppressed collagen- and arachidonic acid-stimulated platelet aggregation, while other agonists thrombin and U46619 were impervious and refractory to GK's effects. Additionally, GK attenuated ATP release, surface exposure of P-selectin, ([Ca2+]i) levels, and thromboxane A2 synthesis in activated platelets. GK also dramatically blunted the activation and phosphorylation of PLCγ2-PKC, PI3K-Akt-GSK3β, and MAPK (ERK, p38, JNK) signaling cascades which are known to promote platelet activation. Notably, these multifaceted inhibitory effects of GK on human platelets were independent of and unaffected by cyclic nucleotide (cAMP, cGMP) regulation. Moreover, in an in vivo study, ginkgetin significantly reduced cerebral infarction in mice subjected to middle cerebral artery occlusion. Collectively, by selectively impeding PLCγ2–PKC signaling, GK potently blocks platelet hyperresponsiveness, activation, and aggregation induced by various stimuli, underscoring its promising translational potential for managing thrombosis and CVDs.