Simvastatin Protects the Dopaminergic Neurons from MPTP-Mediated Injury by Inducing BDNF via PPARα Activation

Parkinson's disease (PD) is a neurodegenerative disease characterized by preferential loss of the dopaminergic neurons in the nigrostriatal pathway. The specific molecular mechanisms for the neuronal loss remain unclear, and no cure currently exists. BDNF is a neurotrophic factor that restores the dopaminergic neurons in variant PD models. Emerging evidence suggests that simvastatin could upregulate BDNF in the brain. This study aimed to assess the neuroprotective effect of simvastatin and delineate its action mechanism. We found that simvastatin rescued the SH-SY5Y cells from MPP⁺ toxicity at 10 nM by upregulating BDNF and activating its downstream signaling pathways, and the protective action was significantly counteracted by BDNF siRNA or TrkB antagonist (K252a). Importantly, simvastatin upregulated BDNF via peroxisome proliferator-activated receptor alpha (PPARα) activation, as silencing the PPARα gene decreased the simvastatin-mediated BDNF upregulation and the cell viability upon exposure to MPP⁺. Next, we evaluated its neuroprotective effects in the PD animal model mediated by MPTP. Pretreatment with simvastatin for 2 weeks attenuated the MPTP-caused loss of the nigrostriatal dopaminergic neurons as determined by immunohistochemical staining for tyrosine hydroxylase. In parallel with the results, simvastatin ameliorated the decrease in the striatal dopamine level and behavioral impairment elicited by the neurotoxicant. Consistent with the in vitro study, simvastatin upregulated BDNF expression and restored the BDNF level in the MPTP-treated striatonigral regions. These findings suggest that simvastatin's neuroprotection may be linked to the upregulation of BDNF via activation of PPARα, and it could be a possible therapeutic intervention for the treatment of PD.