Valproate decreases inositol biosynthesis

Background: Lithium and valproate (VPA) are used for treating bipolar disorder. The mechanisin of mood stabilization has not been elucidated, but the role of inositol has gained substantial support. Lithium inhibition of inositol monophosphatase, an enzyme required for inositol recycling, and de novo synthesis, suggested the hypothesis that lithitum depletes brain inositol and attenuates pbospboinositide signaling, Valproate also depletes inositol in,yeast, Dictyostelium, and rat neurons. This raised the possibility that the effect is the result of myo-inositol-1-phosphate (MIP) synthase inhibition. Methods: Inositol was measured by gas chromatography. Human prefrontal cortex MIP synthase activity was assayed in crude homogenate. INO1 was assessed by Northern blotting. Growth cones morphology was evaluated in cultured rat neurons. Results: We found a 20% in vivo reduction of inositol in mouse frontal cortex after acute VPA administration. As hypothesized, inositol reduction resulted from decreased MIP synthase activity: .21-28 mmol/L VPA reduced The activity by 50%. Among psychotropic drugs, the effect is specfic to VPA. Accordingly, only VPA upregulates the yeast INO1 gene coding FOR MIP synthase. The VPA derivative N-methyl-2.2,3,3-tetramethyl-cyclolpropane carboxamide rcduces MIP synthase activity and has an effect similar to that of VPA on rat neurons, whereas another VPA derivative. valpromide, poorly affects the activity and has no fact on neurons. Conclusions: The rate-linfiting step of inositol biosynthesis, catalyzed by AlIPsynthase. is inhibited by VPA; inositol depletion is cifirst event shown to be common to lithium and VPA.