OBJECTIVE: Valproate (VPA) is effectively used in the treatment of bipolar disorder, although the mechanism of action is unclear. In patients with bipolar disorder, 5-hydroxytryptamine (5-HT)-induced intraplatelet calcium (Ca) mobilization has been shown to be enhanced. METHODS: We examined the effect of VPA on 5-HT-induced Ca response in the platelets of normal subjects, in the presence of a calmodulin antagonist W-7 (N-[6-aminohexyl]-5-chloro-1-naphthalenesulfonamide), a protein kinase C (PKC) activator phorbol 12-myristate 13-acetate (PMA) or PKC inhibitors staurosporine and bisindolylmaleimide II. RESULTS: VPA inhibited the 5-HT-induced Ca response in a concentration-dependent manner. For calmodulin pathways, W-7 enhanced the 5-HT-stimulated Ca response, which was not affected by VPA. For PKC pathways, PMA reduced the Ca response, although both PKC inhibitors had no effect. PMA, staurosporine or bisindolylmaleimide II reversed the inhibitory effect of VPA on the Ca response, while W-7 did not modify it. CONCLUSION: These findings suggest the possibility that the mechanism of action of VPA may be partly related to PKC signalling.
OBJECTIVE:Valproate (VPA) is effectively used in the treatment of bipolar disorder, although the mechanism of action is unclear. In patients with bipolar disorder, 5-hydroxytryptamine (5-HT)-induced intraplatelet calcium (Ca) mobilization has been shown to be enhanced. METHODS: We examined the effect of VPA on 5-HT-induced Ca response in the platelets of normal subjects, in the presence of a calmodulin antagonist W-7 (N-[6-aminohexyl]-5-chloro-1-naphthalenesulfonamide), a protein kinase C (PKC) activator phorbol 12-myristate 13-acetate (PMA) or PKC inhibitors staurosporine and bisindolylmaleimide II. RESULTS:VPA inhibited the 5-HT-induced Ca response in a concentration-dependent manner. For calmodulin pathways, W-7 enhanced the 5-HT-stimulated Ca response, which was not affected by VPA. For PKC pathways, PMA reduced the Ca response, although both PKC inhibitors had no effect. PMA, staurosporine or bisindolylmaleimide II reversed the inhibitory effect of VPA on the Ca response, while W-7 did not modify it. CONCLUSION: These findings suggest the possibility that the mechanism of action of VPA may be partly related to PKC signalling.