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Temporal effects of paraquat/maneb on microglial activation and dopamine neuronal loss in older rats

We investigated the effects of combined systemic exposure to the herbicide paraquat (PQ) and the fungicide maneb (MB) in 6‐month‐old rats, an animal model of Parkinson's disease resulting from environmental toxin exposure. Following two doses of PQ (10 mg/kg) and MB (30 mg/kg), 52% of animals developed fatal lung injury. Examination of the remaining animals showed degeneration of dopaminergic (DA) neurons in the substantia nigra pars compacta 6 weeks, but not 4 weeks, following PQ/MB. In contrast, microglial activation was observed at 4 weeks, but had abated by 6 weeks. Compared with our previous findings in younger rats, these results suggest increased susceptibility of older animals to lung and brain toxicity from PQ/MB exposure. Microglial activation preceded, and therefore likely contributed to, DA neurodegeneration. Further, electron microscopy revealed an abnormal appearance of the Golgi apparatus at 4 weeks that was confirmed using double immunostaining for tyrosine hydroxylase and Golgi. This suggests that PQ/MB causes protein processing dysfunction in nigral DA neurons that may be either a direct effect of PQ/MB or the result of microglial activation.