Transient exposure of rats to rotenone causes delayed, progressive, parkinsonian motor deficits associated with nigrostriatal degeneration, progressive neuroinflammation and synucleinopathy

Abstract BACKGROUND: Individuals with Parkinson’s disease (PD) typically receive a diagnosis once they have developed motor symptoms, at which point there is already significant loss of substantia nigra dopamine neurons, α-synuclein accumulation in surviving neurons, and neuroinflammation. Consequently, the point of clinical presentation may be too late to initiate disease-modifying therapy. In contrast to this clinical reality, animal models often involve acute neurodegeneration and potential therapies are tested concurrently or shortly after the pathogenic insult has begun rather than later when diagnostic clinical symptoms emerge. OBJECTIVE: We sought to develop a model that reflects the clinical situation more accurately. METHODS: Middle-aged rats (7-9 months-old) received a single daily intraperitoneal injection of rotenone for 5 consecutive days and were observed over the next 8-9 months. RESULTS: Rotenone-treated rats showed transient motor slowing and postural instability during exposure but recovered within 9 days of rotenone cessation. Rats remained without behavioral deficits for 3-4 months, then developed progressive motor abnormalities over the ensuing months. As motor abnormalities began to emerge 3 months after rotenone exposure, there was significant loss of nigral dopaminergic neurons and significant microglial activation. There was delayed accumulation of α-synuclein in neurons of the substantia nigra and frontal cortex, which was maximal at 9 months post-rotenone. CONCLUSIONS: A brief, temporally-remote exposure to rotenone causes delayed and progressive behavioral and neuropathological changes similar to Parkinson’s disease. This model mimics the human clinical situation, in which pathogenesis is well-established by the time diagnostic motor deficits appear. As such, this model may provide a more relevant experimental system in which to test disease-modifying therapeutics.