Possible involvement of protein kinase C in the pathophysiology and treatment of bipolar disorder

Over the past decade, the focus of research into the pathophysiology of bipolar disorder has shifted from an interest in the biogenic amines to an emphasis on second messenger systems within cells. Emerging evidence implicates protein kinase C (PKC) intracellular signaling cascade in the pathophysiology and treatment of bipolar disorder. This review explores the possible involvement of PKC in bipolar disorder summarizing results from laboratory and clinical studies. Bipolar patients were demonstrated to have altered PKC levels, activity or distribution in platelets and in the brain. Chronic administration of lithium and valproate produced a striking reduction in protein kinase C (PKC) human cells and in rats. PKC inhibition in animals resulted in altered affective-like behavior and in a small study, tamoxifen (a PKC inhibitor) had marked antimanic efficacy. The results of studies at the molecular, cellular, animal and clinical levels all suggest that regulation of PKC signaling pathways may play a major part in the pathophysiology and treatment of bipolar disorder. Therefore, this pathway may be a promising candidate for the development of new, more specific drugs for the disease.