Ecotoxicology and environmental safetyJan 13, 2026

Activating the SIRT1-Nrf2 pathway may reduce brain inflammation and cell damage to improve memory problems caused by rotenone in mice

Longevity & Aging Weekly Brief ↗PubMed ↗DOI ↗

Updated Jan 14, 2026

Abstract

Rotenone significantly decreased the expression and activation of SIRT1 and Nrf2 in the hippocampus of mice.

Chronic exposure to rotenone is linked to increased risk of Parkinson's disease and cognitive deficits in mice.
Activation of the SIRT1-Nrf2 pathway using resveratrol and tert-butylhydroquinone improved learning and memory impairments caused by rotenone.
Resveratrol and TBHQ reduced inflammation by suppressing microglial activation and lowering proinflammatory gene expression.
The study suggests that activation of the SIRT1-Nrf2 axis may protect against neuronal ferroptosis by decreasing iron accumulation and lipid peroxidation.
These findings indicate that targeting the SIRT1-Nrf2 axis could offer a potential therapeutic strategy for pesticide-induced neurotoxicity.

Simplified

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.

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Competing interests

Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

PubMed

Activating the SIRT1-Nrf2 pathway may reduce brain inflammation and cell damage to improve memory problems caused by rotenone in mice

Abstract

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Funding

Competing interests

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