A longitudinal study of rotenone-induced Parkinsonism in mice

Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by the loss of dopaminergic neurons in the substantia nigra. Environmental toxins such as rotenone are widely used to model PD pathology and evaluate new drugs in PD; however, the long-term consequences of toxin exposure remain poorly understood. Here, we performed a longitudinal mouse study to examine the onset, progression, and long-term outcomes of rotenone-induced PD-like phenotypes. A 21-day regimen of rotenone (2.5 mg/kg/day, intraperitoneal) produced robust Parkinsonism-like phenotypes by week 4, including impaired locomotion, anxiety-like behaviors, and deficits in motor coordination and learning, accompanied by reduced tyrosine hydroxylase (TH) expression and loss of TH + neurons in the substantia nigra pars compacta. Unexpectedly, these behavioral and neuropathological deficits gradually resolved over time. After 12 months of toxin cessation, rotenone-treated mice exhibited behavioral performance and TH expression levels comparable to untreated controls. These findings reveal a previously underappreciated capacity for adaptive resilience within the nigrostriatal dopaminergic system following toxic injury.