Rotenone as Preclinical Model Compound in Parkinson Disease

Abstract

The motor symptoms of Parkinson’s disease (PD) are characterized by a combination of bradykinesia, resting tremor, rigidity, and postural instability, which are caused by striatal dopamine depletion resulting from loss of nigral dopamine neurons and dopaminergic projections. At the time of diagnosis, there is already extensive loss of striatal dopamine and nigral dopamine neurons. Patients also commonly experience a host of cognitive, psychiatric, autonomic, sleep, and sensory disturbances that likely result from pathology to regions outside the substantia nigra. These nonmotor abnormalities may occur decades before diagnosis. “Preclinical” PD is the disease before motor symptom severity elicits a PD diagnosis. Currently, there is an emphasis on the creation and characterization of preclinical models to identify early-stage PD features and test early intervention strategies. The rat rotenone model tests the hypothesis that nigral dopamine neurons are selectively sensitive to systemic mitochondrial complex I inhibition. The model replicates selective loss of nigral dopamine neurons and was the first neurotoxicant model to reproduce intracellular α-synuclein accumulation, similar to Lewy bodies. Subsequent investigations have found the model to replicate many additional PD features. In this chapter, the utility of this model to examine preclinical PD endpoints is evaluated. The major emphasis is pathological and functional alterations that are known to occur in the earliest stages of PD or even be predictive of disease development. Finally, specific rotenone administration regimens to produce preclinical PD models are detailed. In summary, available data suggest that the rat rotenone model is an excellent system to examine preclinical PD.