SODIUM VALPROATE DOWN-REGULATES THE MYRISTOYLATED-ALANINE-RICH-C-KINASE SUBSTRATE (MARCKS) IN IMMORTALIZED HIPPOCAMPAL CELLS - A PROPERTY OF PROTEIN-KINASE-C-MEDIATED MOOD STABILIZERS

Sodium valproate (VPA) is a short-chain fatty acid with well-establish ed anticonvulsant properties and apparent clinical efficacy in the tre atment of bipolar disorder (manic-depressive illness). Little is known regarding the mechanism of action of VPA in the brain that could acco unt for this clinical therapeutic profile. Lithium has been the standa rd treatment for bipolar disorder, and it is known to be an uncompetit ive inhibitor of inositol monophosphatase in the phosphoinositide (PI) signaling cascade at clinically relevant concentrations. Recent studi es have provided data in support of a role for protein kinase C and th e down-regulation of expression of the myristoylated alanine-rich C ki nase substrate (MARCKS) in the long-term therapeutic action of lithium in the brain, which is dependent on both the relative activity of rec eptor-coupled PI signaling and the concentration of myo-inositol. Our current results demonstrated that valproate induces a concentration-an d time-dependent reduction of MARCKS in immortalized hippocampal cells that appears to be independent of both the level of muscarinic recept or-activated PI signaling as well as the concentration of myo-inositol . In CHO-K1 cells transfected with the human mi muscarinic receptor, u nlike lithium, there is no evidence for receptor-mediated accumulation of CMP-PA in the presence of VPA, providing more direct data for its lack of interaction within the PI signaling cascade. The action of VPA on MARCKS occurs within the therapeutic concentrations and time cours e observed in clinical studies of patients with bipolar disorder. Furt hermore, the effect on MARCKS protein is additive in the presence of t herapeutic concentrations of both lithium and valproate, consistent wi th clinical observations regarding the enhanced efficacy of the combin ation treatment. Finally, in studies examining acute and chronic effec ts of a variety of psychotropic compounds and VPA structural analogs, it is evident that the property of regulation of MARCKS is shared by t he mood-stabilizers lithium and VPA, which may be specific to a class of drugs effective in the treatment of bipolar disorder.