Systemic Rotenone Administration Causes Extra-Nigral Alterations in C57BL/6 Mice

Systemic administration of rotenone replicates several pathogenic and behavioural features of Parkinson's disease (PD), some of which cannot be explained by deficits of the nigrostriatal pathway. In this study, we provide a comprehensive analysis of several neurochemical alterations triggered by systemic rotenone administration in the CNS of C57BL/6 mice. Mice injected with either 1, 3 or 10 mg/kg rotenone daily via intraperitoneal route for 21 days were assessed weekly for changes in locomotor and exploratory behaviour. Rotenone treatment caused significant locomotor and exploratory impairment at dosages of 3 or 10 mg/kg. Molecular analyses showed reductions of both TH and DAT expression in the midbrain, striatum and spinal cord, accompanied by altered expression of dopamine receptors and brain-derived neurotrophic factor (BDNF). Rotenone also triggered midbrain-restricted inflammatory responses with heightened expression of glial markers, which was not seen in extra-nigral regions. However, widespread alterations of mitochondrial function and increased signatures of oxidative stress were identified in both nigral and extra-nigral regions, along with disruptions of neuroprotective peptides, such as pituitary adenylate cyclase-activating polypeptide (PACAP), vasoactive intestinal peptide (VIP) and activity-dependent neuroprotective protein (ADNP). Altogether, this study shows that systemic rotenone intoxication, similarly to PD, causes a series of neurochemical alterations that extend at multiple CNS levels, reinforcing the suitability of this pre-clinical model for the study extra-nigral defects of PD.