p38/p53-Mediated Bax induction contributes to neurons degeneration in rotenone-induced cellular and rat models of Parkinson’s disease

Rotenone is an environmental neurotoxin that induces degeneration of dopaminergic (DA) neurons in substantia nigra pars compacta (SNpc), which ultimately results in parkinsonism, but the molecular mechanisms of selective degeneration of nigral DA neurons are not fully understood. In the present study, we investigated the induction of p38^MAPK/p53 and Bax in SNpc of Lewis rats after chronic treatment with rotenone and the contribution of Bax to rotenone-induced apoptotic commitment of differentiated PC12 cells. Lewis rats were subcutaneously treated with rotenone (1.5 mg/kg) twice a day for 50 days and the loss of tyrosine hydroxylase (THase), motor function impairment, and expression of p38^MAPK, P-p38^MAPK, p53, and Bax were assessed. After differentiated PC cells were treated with rotenone (500 nM) for 6–36 h, protein levels of p38^MAPK and P-p38^MAPK, p53 nuclear translocation, Bax induction and cell death were measured. The results showed that rotenone administration significantly reduced motor activity and caused a loss of THase immunoreactivity in SNpc of Lewis rats. The degeneration of nigral DA neurons was accompanied by the increases in p38^MAPK, P-p38^MAPK, p53, and Bax protein levels. In cultured PC12 cells, rotenone also induced an upregulation of p38^MAPK, P-p38^MAPK, p53 and Bax. Pharmacological inhibition of p38^MAPK with SB203580 (25 μM) blunted rotenone-induced cell apoptosis. Treatment with SB203580 prevented the p53 nuclear translocation and upregulation of Bax. Inhibition of p53 with pifthrin-alpha or Bax with siRNAs significantly reduced rotenone-induced Bax induction and apoptotic cell death. These results suggest that the p38^MAPK/p53-dependent induction of Bax contributes to rotenone’s neurotoxicity in PD models.