Abstract
Parkinson's disease (PD) is due to the degeneration of dopamine (DA) neurons and loss of DA and the dopaminergic enzymes, including L‐aromatic aminoacid decarboxylase (LAAD) in the nigrostriatal (NS) system. In our studies we test the hypothesis that timed exposure of fetuses to toxins sensitizes the NS DA neurons and that later challenges further harm the vulnerable neurons, resulting in PD. Thus, a sensitization stage and a precipitating stage underlie idiopathic PD. For the 1st/sensitization stage we exposed C57B/L mouse fetuses to 10mg/kg/dy 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP) during gestation day 8‐12 to target the emerging NS DA neurons. For the 2nd/precipitating stage the adult offspring were challenged with 10, 20 or 30 mg/kg/dy MPTP for 7 days. At 7dy post‐MPTP the analysis of LAAD and DA and its metabolites were performed. The results show that prenatal MPTP has a long lasting effect and may be specific for the NS system, since in the 3mths old offspring striatal and brainstem, but not cortical, LAAD expressions were reduced. Postnatal MPTP is additive and further decreases LAAD in a dose‐dependent manner. Prenatal MPTP did not significantly reduce cortical DA, as compared to PBS but it sensitizes DA to postnatal MPTP in different concentration. The outcome demonstrates that idiopathic PD may have a fetal basis and that chemical and/or functional stress and age‐related changes precipitate PD symptoms by causing further harm. Supported by NIH RO1NS041674 and NIH R21NS049623.
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