Glutamate-induced excitotoxicity has been reported to be involved in the pathophysiology of neurodegenerative disorders. It has been proposed that valproic acid (VPA), which is used in epileptic and bipolar disorders, may be protective against excitotoxic insult. The aim of the present study was to investigate the effects of VPA against the glutamate excitotoxicity in the SH-SY5Y human neuroblastoma cell line and determine its anti-oxidant capacity by measuring oxidative and anti-oxidant biochemical parameters. SH-SY5Y human neuroblastoma cells were pre-treated with 1, 5 or 10 mM VPA prior to exposure to 15 mM glutamate. The MTT assay was performed to determine cell viability. To detect oxidative insult in glutamate toxicity and the potential anti-oxidant effect of VPA, the cell catalase (CAT), superoxide dismutase (SOD), malondialdehyde and hydrogen peroxide (H2O2) activity was determined. A progressive decline in cell viability was observed with increasing glutamate concentrations (1-50 mM). Treatment with 1 mM VPA was revealed to be effective in increasing the viability of cells exposed to glutamate for 24 h. Oxidative damage, including an increase in H(2)O(2)and MDA, was observed in SH-SY5Y cells treated with glutamate and was reduced by pre-treatment with VPA. CAT activity was decreased following glutamate exposure, but VPA did not prevent this decrease. SOD activity was increased by treatment with VPA alone and was not affected by glutamate exposure. Overall, the present results confirmed the critical role of oxidative stress in glutamate-induced excitotoxicity. They also suggested that VPA may exert an anti-oxidant effect against glutamate-induced excitotoxicity by decreasing oxidative parameters, including H(2)O(2)and MDA, but only had a slight effect on CAT and SOD activity, which have an anti-oxidant capacity.