Effects of diet-induced obesity on the neurodegeneration in MPTP-treated mice

초록

Obesity is associated with increase in markers indicating systemic inflammatory condition, however, the effects of obesity on the vulnerability of CNS to the oxidative stress are not fully evaluated. We evaluated the effects of high-fat diet-induced obesity on the neurotoxicity in a well-defined MPTP-induced Parkinsonism model. After 6 weeks of high-fat or matched normal diet, mice were administered subcutaneously 4 low (5mg/kg) or high (15mg/kg) doses of MPTP at 2-hr intervals. The mortality of obese high dose group was higher (75%) than that of lean high dose group (25%). The immunoreactivities of TH and MAP-2 decreased in lean group only at high dose, but did in obese group at both doses of MPTP. The striatal dopamine contents were decreased both in obese and lean groups although the mean dopamine content was slightly lower in obese low dose than lean low dose group (p>0.05). Serum level of NOx in obese mice was significantly lower than that in lean mice (p<0.05), which indicates the bioavailability of nitric oxide (NO) may decrease in obese condition. In Western blot analysis, the levels of nNOS in striatum were neither changed by high-fat diet, while the nNOS phosphorylation was increased by high-fat diet, indicating the decrease of nNOS activity. The immunoreactivity of nitrotyrosine in striatum in obese group was lower than that of lean group in both doses of MPTP. Combined with our results, we suggest that diet-induced obesity may reduce the nitrogenous signal through the nNOS phosphorylation, and possibly deteriorate the protective role of neuronal NO against MPTP-induced neurotoxicity. The more precise mechansisms and effects of the high-fat diet on the role of neuronal NO signals should be further evalutated in the future.