The Effects Of Valproate And Lithium On The Activity Of ERK-1/2 Signal Pathway In Central Nervous System In Vivo

Background: The Bipolar disorder (manic-depressive illness) is a popular, severe, chronic, and life-threatening disorder. The discovery of valproic acid and lithium's efficacy as a mood-stabilizing agent revolutionized the treatment of patients with bipolar illness. Despite valproic acid and lithium's role as one of psychiatry's most important treatments, the molecular and cellular basis for their mood-stabilizing action remains to be elucidated.Objective: In order to study the effects of chronic in vivo valproic acid and lithium administration on ERK-1/2 signaling pathway, and to elucidate the molecular mechanisms underlying the therapeutic effect s of valproic acid and lithium.Methods: Male Wistar rats were divided into three groups (valproic acid, lithium and control, each 20 animals), the experimental group animals were treated with sodium valproate (3.6 g/kg) or lithium carbonate (2.4/kg) chow for 4 weeks, and control group animal had access to normal chow. By the end of the 4th week, rat brains were removed immediately on decapitation and dissected on ice, and the hippocampus and frontal cortex were obtained. The total proteins or nuclear proteins of rat brain hippocampus and frontal cortex were prepared. The phosphorylated Levels of MEK, ERK-1/2, RSK1 and CREB, and the expression levels of BCL-2 and BAX were assayed by western blot analysis. DNA binding activity of transcriptional factor AP1 was determined by EMSA.Results: Either Valproic acid or lithium increased the activities of MEK, ERK-1/2, RSK1, CREB and up-regulated the expression of BCL-2 in rat brain hippocampus and frontal cortex. In addition, Valproic acid could increase the activities of AP1 and lithium could decrease the expression of Bax in rat brain hippocampus and frontal cortex.Conclusion: These data suggest that chronic treatment of either valproic acid or lithium activates ERKs signaling pathway, and up-regulates the expression of BCL-2 proteins or down-regulates the expression of BCL-2 proteins in central nerve system (CNS), which may associate with the therapeutic efficacy of valproic acid and lithium in the treatment of manic-depressive illness.