Acceleration of MPTP-induced Neurotoxicity in Obese Mice: nNOS phosphorylation and Mn-SOD activity

초록

Currently, obesity is considered as a systemic inflammatory condition. In a previous epidemiologic study, midlife adiposity is associated with an elevated risk of future Parkinson’s disease. However, the effects of obesity on the vulnerability of central dopaminergic system against exposure to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridin (MPTP) are not fully defined. Furthermore, although the neuronal nitric oxide (NO) signaling is closely associated with the food intake and dopamine homeostasis, the effects of alteration of NO signal on the susceptibility of dopaminergic neurons to neurotoxins are not determined. Recently, it was reported that the phosphorylation of neuronal NO synthase (nNOS) produced the decreased activity of nNOS. In this study, we evaluated the susceptibility of obese mice to acute dopaminergic toxicity of MPTP. After induction of obesity by high-fat diet for 12 weeks, single intraperitoneal dose of MPTP were administered and biochemical assays were conducted at 24hrs after MPTP administration. After 12 weeks, the plasma NOx (nitrate and nitrite) level in obese mice was higher than that of lean mice indicating the production of systemic inflammation. The striatal dopamine content was significantly decreased in obese mice by MPTP compared with that of lean mice. As the phosphorylation of nNOS, the trend of increase in phosphorylation of nNOS in obese mice was observed. Furthermore, the mitochondrial superoxide dismutase (Mn-SOD) was inhibited only in obese mice. Combined our present and previous (modest obese model) results, the mechanisms of increased vulnerability of dopaminergic system against the MPTP in obese mice considering the phosphorylation of nNOS and alteration of Mn-SOD activity will be discussed. (Supported by BK-21)