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.