AIM To investigate whether pioglitazone can protect cortical neurons from lipopolysaccharides(LPS)-induced neurotoxicity and the mechanisms responsible for this protective effect. METHODS After 7 d cultures，cultured cortical neurons were incubated with LPS 10 mg·L~(-1) for 4-24 h with or without other drugs. In co-incubation experiments, other drugs were added to the neurons 30 min or 1 h prior to incubation with LPS. The cell viability was assessed by MTT assay. The neuronal apoptosis was quantified by scoring the percentage of cells with apoptotic nuclear morphology after Hoechst 33258 staining. The cultured cells were then fixed on the 7th day and immunocytochemically stained with phosphorylated JNK1 antibody. The protein expressions of active caspase 3 and phosphorylated JNK1 were measured by Western blot. Nitric oxide (NO) generation was measured by Griess method. RESULTS The decrease of cell viability and the increase of apoptotic cells in cultured cortical neurons were observed incubated with LPS for 24 h compared with the normal controls. The cell viability of cortical neurons was decreased from (100.0±10.9)% in the normal control group to (72.3±2.1)% in the LPS-treated group and the apoptotic cell percentages were increased from (11.5±4.2)% in the normal control group to (39.5±8.2)% in the LPS group. LPS induced the increases in phospho-JNK1, active caspase 3 expression, and NO generation. Pioglitazone 0.01, 0.1 and 1 μmol·L~(-1), respectively inhibited LPS-induced decrease in cell viability and increase of apoptotic morphology, active caspase 3 expression in cultured neurons. In LPS+pioglitazone 1 μmol·L~(-1) group, cell viability was （97.8±9.7）%, the apoptotic cells percentage was (20.6±5.0)%, NO generation (6.8±1.3)μmol·L~(-1). Furthermore, pioglitazone also inhibited LPS-induced the increase in JNK1 phosphorylation and NO generation. JNK inhibitor SP600125 5 μmol·L~(-1) significantly inhibited LPS-induced neurotoxicity, cell viability was increased from (72.3±2.1)% to (109.8±11.8)%, the apoptotic cells percentage from (39.5±8.2)% decreased to (19.1±4.8)%, NO generation from （21.1±5.0）μmol·L~(-1) decreased to（4.0±1.3）μmol·L~(-1). The PPARγ antagonist GW9662 10 μmol·L~(-1) did not reverse the effects of pioglitazone. In LPS+pioglitazone 1 μmol·L~(-1)+GW9662 10 μmol·L~(-1) group, cell viability was (90.7±6.9)%, the apoptotic cells percentage was (23.4±4.1)%, and NO concentration was (5.8±0.7)μmol·L~(-1). CONCLUSION Pioglitazone protects cortical neurons against LPS insult at least via inhibiting JNK activity and NO generation, but not PPARγ activation.