The acute effect of valproate on cerebral energy metabolism in mice

Sodium valproate (VPA) is used in the acute treatment of status epilepticus and mania. We studied the acute effect of VPA on cerebral energy metabolism in awake mice that received VPA 400 mg kg(-1) and [1-(13)C]glucose or [2-(13)C]acetate. At 25 min, (13)C NMR spectroscopy of brain extracts indicated inhibition of the tricarboxylic acid (TCA) cycle, as could be seen from the accumulation of [4-(13)C]glutamate and reduction in [(13)C]aspartate formation. Concomitantly, the level of ATP was reduced by 40%. To identify the enzymatic step at which the TCA cycle was inhibited [U-(14)C]alpha-ketoglutarate was injected intracerebrally. Inhibition of alpha-ketoglutarate dehydrogenase was evident at 25 min, as shown by accumulation of [(14)C]glutamate. At 45 min the inhibition of alpha-ketoglutarate dehydrogenase was reversed, shown by both (13)C- and (14)C-labeling, and the ATP level was normalized. The study shows for the first time that acute administration of VPA causes inhibition of the TCA cycle activity in vivo. The reduction in brain ATP would be expected to reduce neuronal excitability through modulation of sodium channels which may be clinically advantageous in the initial phase of VPA treatment.