The activation of SIRT1-Nrf2 axis exerts beneficial effects against rotenone-induced cognitive deficits in mice through inhibition of neuroinflammation and ferroptosis.

Rotenone, a widely used agricultural pesticide has been linked to an increased risk of Parkinson's disease (PD) following chronic exposure. Our previous study found that rotenone not only caused motor deficits in mice, but was also able to cause cognitive deficits, a common non-motor symptom in PD. This study aimed to explore whether activation of the SIRT1-Nrf2 axis confers neuroprotection against rotenone-induced cognitive impairments. We found that rotenone significantly decreased the expression and activation of SIRT1 and Nrf2 in the hippocampus of mice. Pharmacological activation of SIRT1 and Nrf2 using resveratrol and tert-butylhydroquinone (TBHQ), respectively, markedly ameliorated rotenone-induced learning and memory impairments and neuronal damage. Mechanistically, resveratrol and TBHQ suppressed microglial activation and the expression of proinflammatory genes (iNOS, TNFα, IL-1β), attenuated C3-CR3 signaling, and restored the levels of synaptic proteins (PSD95, mBDNF, TrkB), indicating suppression of abnormal glia-mediated synaptic pruning. Furthermore, SIRT1-Nrf2 axis activation reduced iron accumulation and lipid peroxidation in the hippocampus, accompanied by increased GPX4 and decreased COX2 and ACSL4 expression, suggesting suppression of neuronal ferroptosis. Collectively, our findings demonstrate that activation of the SIRT1-Nrf2 axis alleviates rotenone-induced cognitive deficits by inhibiting microglia-mediated synaptic pruning and neuronal ferroptosis. These results provide mechanistic insight and a potential therapeutic target for pesticide-induced neurotoxicity and PD-related cognitive dysfunction.