Curcumin Modulates p62-Keap1-Nrf2-Mediated Autophagy in Rotenone-Induced Parkinson's Disease Mouse Models

Autophagy mediates self-digestion of abnormally aggregated proteins and organelles present in the cytoplasm. This mechanism may prove to be neuroprotective against Parkinson's disease (PD) by clearing misfolded α-synuclein (α-syn) aggregates from dopaminergic neurons. p62, an adaptor protein acts as a selective substrate for autophagy and regulates the formation as well as the degradation of protein aggregates. p62 sequesters keap1 freeing Nrf2 and consequently activating the transcription of its target genes. In the present study, we aimed to investigate the anti-parkinsonian activity of curcumin targeting primarily activation of autophagy via the Nrf2-Keap1 pathway. The mice were subcutaneously injected with rotenone (2.5 mg/kg bodyweight) and co-treated with oral administration of curcumin (80 mg/kg bodyweight) for 35 days. Following completion of dosing, motor activities, anti-oxidative potential, mitochondrial dysfunction, and various protein expressions, including Nrf2, Keap1, p62, LC3, Bcl2, Bax, and caspase 3, were assessed. The results revealed that curcumin restored the motor coordination and anti-oxidative activity while improving the mitochondrial functioning in PD mice. Autophagy was evaluated by the change in the expression of autophagic markers, p62 and LC3-II. Reduced p62 and LC3-II expressions in the rotenone mouse model of PD confirmed the compromised autophagy pathway, consequently increasing the aggregation of misfolded protein α-syn. Whereas, curcumin treatment-enhanced autophagy-mediated clearance of misfolded α-syn proteins by increasing the LC3-II expression and blocked apoptotic cascade. Curcumin administration upregulated the Nrf2 expression and normalized the Nrf2-Keap1 pathway, which justifies the improved anti-oxidative activity. Therefore, the findings reveal that curcumin is a Nrf2-inducer and is endowed with neuroprotective potential, which may prove to be a potential candidate for the anti-Parkinson's disease treatment therapy.