Abstract: Objective To investigate the effect of N-acetyl-cysteine (NAC) and depakine (DP) on the changes of membrane potential and peroxidate in rat cortex neurons exposed to ferrous chloride (FeCl2). Methods Cultured cortex neurons of newly born SD rats were randomly divided into control group (PBS group), model group (FeCl2 group), NAC pretreatment group (NAC group), DP pretreatment group (DP group) and NAC+DP pretreatment group (NAC+DP group). In the latter three groups, NAC (0.08 mg/ml) and DP (0.1 mg/ml) were added in the cell culture 2 and 3 h before FeCl2 (1 mmol/L) exposure, respectively. After exposure to FeCl2, the membrane potential of the neurons was detected with fluorescent dye DiBAC4 (3) (bis-(1,3-dibutylbarbituric acid) trimethine oxonol), and the peroxidate level with 2,7-dichlorofluorescin diacetate (H2DCF) by laser confccal scanning microscope (LCSM) and nuclear factor-κB (NF-κB) level with immunocytochemistry. Results Compared with FeCl2 group, the expression of NF-κB and peroxidate level in the neurons were decreased significantly in NAC and NAC+DP groups (P<0.01), but not in DP group (P>0.05). FeCl2 depolarized the membrane potential and increased the expression of NF-κB in the neurons. Compared with FeCl2 group, significant changes in the membrane potential were observed in DP and NAC+DP groups (P<0.01) but not in NAC or PBS group (P>0.05). Conclusions Both NAC and DP can protect the neurons from FeCl2-induced damage but through different pathways, and their combined use can significantly alleviate neuronal damages due to FeCl2 exposure. Antioxidants such as NAC in combination with antiepileptic drugs may produce favorable effect in prevention and treatment of posttraumatic epilepsy.