Age‐related irreversible progressive nigrostriatal dopaminergic neurotoxicity in the paraquat and maneb model of the Parkinson's disease phenotype

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Abstract
While advancing age is the only unequivocally accepted risk factor for idiopathic Parkinson's disease, it has been postulated that exposure to environmental neurotoxicants combined with ageing could increase the risk for developing Parkinson's disease. The current study tested this hypothesis by exposing C57BL/6 mice that were 6 weeks, 5 months or 18 months old to the herbicide paraquat, the fungicide maneb or paraquat + maneb, a combination that produces a Parkinson's disease phenotype in young adult mice. Paraquat + maneb‐induced reductions in locomotor activity and motor coordination were age dependent, with 18‐month‐old mice most affected and exhibiting failure to recover 24 h post‐treatment. Three months post‐treatment, reductions in locomotor activity and deficits in motor coordination were sustained in 5‐month‐old and further reduced in 18‐month‐old paraquat + maneb groups. Progressive reductions in dopamine metabolites and dopamine turnover were greatest in 18‐month‐old paraquat + maneb and paraquat groups 3 months post‐treatment. Increased tyrosine hydroxylase enzyme activity compensated for striatal tyrosine hydroxylase protein and/or dopamine loss following treatment in 6‐week‐old and 5‐month‐old, but not 18‐month‐old paraquat and paraquat + maneb mice. Numbers of nigrostriatal dopaminergic neurons were reduced in all age groups following paraquat alone and paraquat + maneb exposure, but these losses, along with decreases in striatal tyrosine hydroxylase protein levels, were progressive in 18‐month‐old paraquat and paraquat + maneb groups between 2 weeks and 3 months post‐exposure. Collectively, these data demonstrate enhanced sensitivity of the ageing nigrostriatal dopamine pathway to these pesticides, particularly paraquat + maneb, resulting in irreversible and progressive neurotoxicity.