The study investigates the mechanisms of rotenone toxicity in models of Parkinson's disease (PD). Rotenone, a complex I inhibitor, causes selective nigrostriatal dopaminergic degeneration and α-synuclein-positive cytoplasmic inclusions in rats. Using three model systems—SK-N-MC human neuroblastoma cells, chronic midbrain slice cultures, and rotenone-treated animals—the researchers found that rotenone toxicity is mediated by oxidative damage rather than bioenergetic defects. In SK-N-MC cells, rotenone caused dose-dependent ATP depletion and oxidative damage but not cell death, which was prevented by antioxidants. In midbrain slice cultures, rotenone induced oxidative damage and dopaminergic neuronal loss, which was blocked by α-tocopherol. In rotenone-treated animals, oxidative damage was observed in the midbrain and olfactory bulb, regions affected by PD. These findings suggest that oxidative damage plays a crucial role in rotenone toxicity and support the evaluation of antioxidant therapies for PD.The study investigates the mechanisms of rotenone toxicity in models of Parkinson's disease (PD). Rotenone, a complex I inhibitor, causes selective nigrostriatal dopaminergic degeneration and α-synuclein-positive cytoplasmic inclusions in rats. Using three model systems—SK-N-MC human neuroblastoma cells, chronic midbrain slice cultures, and rotenone-treated animals—the researchers found that rotenone toxicity is mediated by oxidative damage rather than bioenergetic defects. In SK-N-MC cells, rotenone caused dose-dependent ATP depletion and oxidative damage but not cell death, which was prevented by antioxidants. In midbrain slice cultures, rotenone induced oxidative damage and dopaminergic neuronal loss, which was blocked by α-tocopherol. In rotenone-treated animals, oxidative damage was observed in the midbrain and olfactory bulb, regions affected by PD. These findings suggest that oxidative damage plays a crucial role in rotenone toxicity and support the evaluation of antioxidant therapies for PD.