Effects of Diet-induced Obesity on the Neurodegeneration in MPTP-treated Mice

초록

Although obesity is associated with increase in markers indicating systemic inflammation, the effects of obesity on the vulnerability of CNS to oxidative stress are not fully evaluated. We evaluated the effects of high-fat (HF) diet-induced obesity (DIO) for 8 weeks on the neurotoxicity in a well-defined MPTP-induced Parkinsonism model. After 8 weeks of diet, mice were administered s.c. with 4 low or high doses of MPTP at 2-hr intervals. The mortality of DIO high dose groups (ObH) was higher (75%) than that of lean high dose group (LH; 50%). The immunoreactivities of TH decreased in lean group at high dose only, but in DIO group at both doses of MPTP. Microtubule associated protein (MAP)-2 expression levels decreased in both diet groups. The mean DA content was lower in DIO-low dose group than that of lean-low dose group (p<0.05), although the striatal DA contents were decreased both in DIO and lean groups. Serum level of NOx in DIO was significantly higher than that in lean mice (p<0.05), which may indicate the inflammatory condition induced in the obese condition. The expression levels of nNOS in striatum were neither changed by HF diet nor MPTP, while the nNOS phosphorylation was increased in HF diet group, indicating the decrease of nNOS activity. And more importantly, the level of Mn-SOD in substantia nigra was significantly decreased in DIO group. Combined with our results, we suggest that DIO may reduce the nitrogenous signal through the nNOS phosphorylation, and possibly deteriorate the protective role of neuronal NO against MPTP-induced neurotoxicity. Furthermore, DIO-induced decrease in Mn-SOD level may put the dopaminergic neurons to the more susceptible condition to neurotoxin. The more precise mechanisms of these effects of the HF diet on the role of neuronal NO signals and antioxidant enzymes should be further evaluated.