Valproate inhibits oxidative damage to lipid and protein in primary cultured rat cerebrocortical cells

Abstract

Valproate is often prescribed as a long-term therapeutic mood stabilizing agent for individuals with bipolar disorder. Although research suggests that this drug may produce a neuroprotective effect, its neuroprotective mechanism is not yet clear. The purpose of this study was to determine if valproate provides a neuroprotective effect against damage caused by oxidative stress in primary cultured rat cerebral cortical cells. We found that chronic treatment with valproate at therapeutically relevant concentrations for 7 days inhibited lipid peroxidation and protein oxidation induced by treatment with 0.25 mM oxidant FeCl 3 for 90 min, indicating that valproate inhibits oxidative damage to lipid and protein. Our results suggest that chronic treatment with valproate may protect neuronal cells from damage caused by oxidative stress and that neuroprotection from oxidative damages may be involved in the mechanism of action of valproate. Supporting this possibility are recent findings that chronic treatment with valproate increased the expression of endoplasmic reticulum stress protein GRP78 (Mol Pharmacol 55 (1999) 521) and antiapoptotic factor bcl-2 (J Neurochem 72 (1999) 379) in rat cerebral cortex. Since GRP78 binds Ca 2+ and folds damaged protein, bcl-2 stabilizes mitochondrial transmembrane potential and inhibits cytochrome C release, and both GRP78 and bcl-2 have been shown to inhibit oxyradical accumulation, together these findings indicate that valproate may target one or more of these processes in order to produce neuroprotective effects.