TY - JOUR T1 - Valproic acid induces monoamine oxidase A via Akt/FoxO1 activation JF - Molecular Pharmacology JO - Mol Pharmacol DO - 10.1124/mol.111.072744 SP - mol.111.072744 AU - Jason Boyang Wu AU - Jean C. Shih Y1 - 2011/07/20 UR - http://molpharm.aspetjournals.org/content/early/2011/07/20/mol.111.072744.abstract N2 - Valproic acid (VPA) has been widely used in clinics for the treatment of multiple neuropsychiatric disorders, such as epilepsy and bipolar disorder. One of the mechanisms by which VPA exerts its effect is through regulating the brain levels of serotonin. However, the molecular basis of this VPA action is not fully understood. Here, we report for the first time that VPA activates monoamine oxidase (MAO) A catalytic activity, mRNA level and promoter activity. MAO A is a key enzyme which degrades a number of monoamine neurotransmitters including serotonin. Our results show that VPA increased the phosphorylation of both Akt and FoxO1, whereas pretreatment of cells with LY294002 (a PI3K inhibitor) reduced the VPA activation of MAO A. Overexpression of FoxO1 dramatically repressed both the basal and VPA-induced MAO A catalytic and promoter activities to 30-60%. siRNA knockdown of FoxO1 attenuated the stimulating effect of VPA on MAO A. Moreover, introduction of a constitutively active form of FoxO1 abolished the activation of MAO A by VPA and Akt. These results suggest that FoxO1 is a repressor for MAO A transcription and its phosphorylation is involved in VPA activation of MAO A. Sequence analysis, electrophoretic mobility shift and chromatin immunoprecipitation assays further showed the presence of a functional FoxO1-binding site in MAO A core promoter. Taken together, these results demonstrate that MAO A is a novel target for VPA via Akt/FoxO1 signaling pathway. This information provides new insights into the pharmacological mechanisms and therapeutic implications of VPA action. ER -