Abstract: Objective To study the protective effect of enhanced peroxisome proliferator activated receptor γ (PPARγ) pathway against apoptosis of long-term cultured primary nerve cells. Methods A natural aging model was established in primary rat nerve cells by long-term culture for 22 days. The cells were divided into control group, 0.1, 1.0, 5.0, and 10 μmol/L GW9662 intervention groups, and 0.1, 1.0, 5.0, and 10 μmol/L pioglitazone intervention groups. The cell viability was assessed using MTT assay and the cell morphological changes were observed after the treatments to determine the optimal concentrations of GW9662 and pioglitazone. Double immunofluorescence labeling and flow cytometry were used to observe the changes in the number of viable cells and cell apoptosis following the treatments; immunocytochemical staining was used to assess the changes in the anti-oxidation ability of the treated cells. Results The optimal concentrations of GW9662 and pioglitazone determined based on the cell viability and morphological changes were both 1 μmol/L. Compared with the control group, GW9662 treatment significantly lowered while pioglitazone significantly increased the total cell number and nerve cell counts (P<0.05), and nerve cells in the cell cultures maintained a constant ratio at about 80% in all the groups (P>0.05). GW9662 significantly enhanced while pioglitazone significantly lowered the cell apoptosis rates compared with the control group (P< 0.05). GW9662 obviously lowered SOD activity and GSH content in G group (P<0.05) and increased MDA content in the cells (P<0.05), and pioglitazone resulted in reverse changes in SOD, GSH and MDA contents in the cells (P<0.05). Conclusion Activation of PPARγ pathway protects long-term cultured primary nerve cells by enhancing cellular anti-oxidant capacity and reducing cell apoptosis, suggesting a potential strategy for anti-aging treatment of the nervous system through intervention of the PPARγ pathway.