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Prenatal and Postnatal Depletion of Tyrosine Hydroxylase by MPTP as a “Sensitization and Precipitation” Model for Parkinson's disease
Author(s) -
Muthian Gladson,
Mackey Veronica,
King Jennifer,
Charlton Clivel
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.1_supplement.715.1
Subject(s) - mptp , tyrosine hydroxylase , sensitization , fetus , endocrinology , dopamine , medicine , parkinson's disease , chemistry , dopaminergic , disease , neuroscience , psychology , biology , pregnancy , genetics
Parkinson's disease (PD) is due to the degeneration of dopamine (DA) neurons and loss of DA and tyrosine hydroxylase (TH) in the nigrostriatal (NS) system. In this project 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 1 st sensitization stage we exposed C57 black mouse fetuses to 10 mg/kg/day 1‐methyl‐4‐phenyl‐1, 2, 3, 6‐ tetrahydropyridine (MPTP) during gestation day 8–12 to target the emerging NS DA neurons. For the 2 nd precipitating stage the adult offsprings were challenged with 10, 20 or 30 mg/kg/day MPTP for 7 days. On the 6 th day post‐MPTP Western blot analysis of brain TH and histology were performed. The results show that prenatal MPTP affects the NS in a long lasting manner, since in the 3 months old adult, striatal and midbrain TH expressions were still reduced by over 26%. Postnatal MPTP is additive and further decreases TH in a dose‐dependent manner. Prenatal PBS or MPTP, plus postnatal MPTP at 10, 20, 30 mg/kg, reduce striatal TH by 0, 52, 79% or 55, 72 and 91%, respectively. 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 further damaging the NS DA neurons that were made susceptible earlier in life. Supported by NIH RO1NS041674 and NIH R21NS049623