Chronic exposure to rotenone, a dopaminergic toxin, results in peripheral neuropathy associated with dopaminergic damage

Abstract

Rotenone, a widely used pesticide, causes a syndrome in rats that replicates, both pathologically and behaviorally, the symptoms of Parkinson's disease (PD). In the present study, we sought to determine if a chronic exposure to rotenone, resulting in dopaminergic loss, could also lead to peripheral neuronal damage related to motor dysfunction. Adult male Sprague-Dawley rats (n=14) were treated with rotenone (1 or 2mg/kg, s.c., once daily) on days 1, 3, 6, 8, 10, 13, 15, 17, 21, 22, and 27 to minimize mortality. Control rats received vehicle (DMSO) injections. Animals were weighed on the days of injection and monitored daily. A mortality of 21% was observed in rotenone treated rats. The motor nerve conduction velocity (MCV) was assessed using action potentials detected from the tail muscle through surface receiver electrodes installed around the distal portion of the tail. Rats exposed to rotenone often developed hind limb paresis with a significant decrease in MCV as detected in tail nerves (p<0.05). Animals were then sacrificed, either 24h after rotenone exposure on day 6 or 24h after the last dose of rotenone on day 27. The striatum and sciatic nerves were dissected on dry ice and flash-frozen and kept at −80°C until further analysis. Striatal dopamine (DA) was analyzed using HPLC-ECD and sciatic nerve pathology was analyzed for neurodegeneration. A time-dependent rotenone-induced striatal depletion of DA (60% after 7 days and 80% after 27 days) was observed. Furthermore, Neurofilament-neurofilament B, Flouro-Jade C and myelin basic protein analyses suggested a time-dependent rotenone-induced neurodegeneration in sciatic nerves. These data, for the first time, indicate an association between dopaminergic damage and peripheral motor nerve degeneration in an animal model of dopaminergic toxicity. Peripheral motor nerve dysfunction in rats following a chronic exposure to rotenone may serve not only as a relevant experimental model of motor neuropathy but also as a peripheral marker of dopaminergic neuronal damage to the central nervous system.