Parkinsonism Reversal and Dopaminergic Resilience: Lessons from a Rotenone-induced Parkinson’s Disease Model

Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterized by profound loss of dopaminergic (DA) neurons, yet the underlying mechanism remains incompletely defined. Mitochondrial toxins can induce acute degeneration of DA neurons and Parkinsonism-like phenotypes in animal models, and epidemiological studies have linked pesticide exposure to increased PD risk; however, the long-term effects of pesticide exposure remain elusive. Here, we examined both the acute and long-term effects of rotenone exposure in mice to understand PD onset, progression, and recovery. A 21-day regimen of rotenone intraperitoneal injections (2.5 mg/kg/day) induced robust Parkinsonism-like deficits by the 4 th week, including impaired locomotion, increased anxiety-like behaviors, and deficits in motor balancing and coordination. These behavioral abnormalities were accompanied by pronounced reduction in tyrosine hydroxylase (TH) expression and selective loss of DA neurons in the substantia nigra pars compacta (SNc). Unexpectedly, these functional impairments fully resolved by 12 months, and rotenone-treated mice behaved equally well as age-matched controls. In parallel, the TH expression and DA neuron density in SNc were restored to control levels. Together, these longitudinal results demonstrate that chronic rotenone injection induces robust but reversible Parkinsonism in the acute phase, with limited long-term consequence on Parkinsonism upon toxin cessation. These findings contrast with the prevailing view that environmental pesticide exposure irreversibly drives PD and instead they reveal a substantial resilience and adaptive capacity of the nigrostriatal dopaminergic system in vivo. Highlights Chronic rotenone exposure in mice induces robust Parkinsonism-like behaviors in both motor and non-motor domains. SNc dopaminergic neurons are reduced by ∼40% at the acute phase within 4 weeks. Both motor and non-motor deficits are fully recovered by 12 months. PD-like pathological changes in the SNc are resolved by 12 months. Infographics