Diindolylmethane ameliorates platelet aggregation and thrombosis: In silico, in vitro, and in vivo studies.

Diindolylmethane (DIM), a major metabolite of indole-3-carbinol (I3C), plays a vital role in the pharmacological actions of I3C. The role of DIM in the inhibition of platelet aggregation and thrombus generation is yet to be revealed. However, how DIM and I3C modulate the interaction of platelets with the glycoproteinVI (GPVI) and purinergic receptor Y 12 (P 2 Y 12) receptors is unknown. In silico studies revealed that the indole group of DIM and indole and the hydroxyl group of I3C are responsible for modulating platelet interaction with GPVI and P 2 Y 12 receptors. In silico studies further predicted that DIM more superiorly modulates platelet interaction with GPVI and P 2 Y 12 receptors than I3C. In vitro studies identified that DIM significantly inhibited platelet aggregation induced by adenosine diphosphate (ADP), collagen, thrombin, and arachidonic acid, increasing the thrombin-induced clot retraction size and clot retraction weight. Moreover, in vivo results of ferric chloride (FeCl 3) induced carotid artery thrombus generation indicate that DIM significantly reduced the reactive oxygen species (ROS), hydrogen peroxide (H 2 O 2), thromboxane 2 (TXB 2), cyclooxygenase 1 (COX-1), prostaglandin E2 (PGE 2), thrombus weight, increased the cyclic adenosine monophosphate (cAMP), and extended the time to occlusion (TTO). Furthermore, DIM did not show thrombolytic activity. Therefore, DIM acts as an antiplatelet aggregation and antithrombotic agent. Moreover, DIM is responsible for the antiplatelet aggregation and antithrombotic activity of I3C. Therefore, DIM could be used to treat thrombotic diseases. [Display omitted] • DIM in in silico studies modulated the GPVI and P 2 Y 12 receptors interactions with platelets. • DIM ameliorated the platelet aggregation induced by ADP, collagen, thrombin, and AA. • DIM not show thrombolytic activity. • DIM mediates the antiplatelet and antithrombotic activities of I3C. • DIM act as a potent antiplatelet and antithrombotic agent than I3C. [ABSTRACT FROM AUTHOR]