Chronic treatment with mood stabilizers lithium and valproate prevents excitotoxicity by inhibiting oxidative stress in rat cerebral cortical cells

Background: Recent studies indicate that chronic treatment with the mood-stabilizing drugs lithium and valproate produces a neuroprotective effect against excitoxicity. In this study, we aimed to determine whether inhibiting oxidative dmage plays a role in a neuroprotective effect of lithium and valproate against excitoxity. Methods: Intracellular free calcium concentration was measured with the fluorescent calcium ion indicator fluo-3. Malondialdehyde, an end product derived from peroxidation of polyunsaturated fatty acid, and protein carbonyls were used to assess oxidative damage to lipid and protein. Excitotoxicty was assayed by measuring cell viability with MTT [3-(4,5-dimethylthiazol-2yl)-2,5-diphenyl tetrazolium bromide] method and by measuring deoxyribonucleic acid (DNA) fragmentation with TUNEL (terminal deoxynucleotidyltransferase-meditated deoxyuridine triphosphate nick end labelling) staining. Results: We found that chronic treatment with lithium and valproate at their terapeutically relevant concentrations significantly inhibited the glutanate-induced increase of intracellular free calcium concentration, lipid peroxidation, protein oxidation, DNA fragmentation, and cell death in primary cultured rat cerebral cortical cells. This treatment had no effect on basal intracellularfree calcium concentration, lipid peroxidation, protein oxidation, DNA fragmentation, and cell death. Conclusion: Our results sugegest that chronic treatmentwith lithiumand valproate inhibits oxidative damage to lipid and protein and in turn produces a neuroprotective effect against excitotoxicity.