고지방 비만이 MPTP 투여 흰쥐에서 신경독성에 미치는 영향

초록

Currently, obesity is considered a systemic inflammation; however, the effects of obesity on the vulnerability of dopaminergic neurons against oxidative stress are not fully defined. We evaluated the effects of high-fat diet-induced obesity (HF DIO) on neurotoxicity in mice treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Eight weeks after a HF or matched normal diet, a severe decrease in levels of striatal dopamine, and of nigral microtubule-associated protein 2 (MAP-2), manganese superoxide dismutase (Mn-SOD) and tyrosine hydroxylase (TH) was observed in obese mice treated with subtoxic doses of MPTP (20 mg/kg) compared with those of the matched lean group. In addition, the levels of nitrate/nitrite (NOx) and thiobarbituric acid-malondialdehyde adducts in substantia nigra of obese mice were reciprocally elevated or suppressed by MPTP. Interestingly, striatal nNOS phosphorylation and dopamine turnover were elevated in obese mice following MPTP treatment, but was not observed in lean mice. The nitrotyrosine immunoreactivity for evaluation of nigral nitrogenous stress in obese mice with MPTP was higher than that in matched lean mice. At higher doses of MPTP (60 mg/kg), the mortality was higher in obese mice than lean mice. These results suggest that DIO may increase the vulnerability of dopaminergic neurons to MPTP via increased levels of reactive oxygen and nitrogen species, and the roles of nNOS phosphorylation on the MPTP toxicities and dopamine homeostasis should be further evaluated.