Effect of ascorbic acid on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced toxicity in the brain of Balb/C mouse

Parkinson's disease (PD), one of the major neurodegenerative diseases, is characterized by degeneration of dopaminergic (DAergic) neurons in the nigrostriatal pathway. Among the various treatments, levodopa (L-dopa) is the one of the most common therapeutic drugs used, however, it only alleviates certain symptoms and it cannot cure the disorder due to its degenerative nature and the uncertain causes of the disease. Animal models, therefore, were developed to investigate the mechanism of PD in order to obtain better and more effective treatments for the disease.; 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is one of the common toxin-induced models of PD used in the investigation on the neuropathology of the disease. During the metabolism of MPTP, various reactive oxidative species (ROS), including superoxide radical and hydrogen peroxide, are produced, and these are believed to cause neuron degeneration. Moreover, its free radical metabolite 1-methyl-4-phenylpyridinium (MPP+), generated in astrocytes, is taken up into DAergic neurons clustered in the substantia nigra (SN) and striatum (ST), and its accumulation leads to neurodegeneration in the nigrostriatal pathway.; In this study, Balb/C mice were used to investigate the protective mechanism of ascorbic acid (AA), a well established antioxidant, against MPTP-induced toxicity in the SN and ST, the most affected brain areas in PD. As antioxidant enzymes are responsible for the removal of ROS, we examined the effect of MPTP on the antioxidant enzymes, superoxide dismutase (SOD) and glutathione peroxidase (GSX), in the SN and ST. As expected, the antioxidant enzymes were induced by MPTP treatment, most likely a physiological response to scavenge the free radicals generated from MPTP, and the induction in the SN was higher than that in the ST. Prolonged AA pretreatment partly reduced the MPTP induction effect, and this may be due to antioxidative effect of AA in scavenging free radicals.; Other than superoxide radical and hydrogen peroxide, MPP+ is another ROS produced from MPTP. In order to investigate the protective effect of antioxidant on MPTP-induced oxidation, AA was administered into MPTP-treated mice and its effect on the generation and metabolism of MPP + was investigated. Following the treatment with AA (100 mg/kg body weight) for 7 days, the levels of AA were both increased in the SN and ST, suggesting that dietary AA can alter the level of AA in the brain. This increment in AA level correlated well with the increased expression of the AA transporter, sodium-dependent vitamin C transporter 2 (SVCT2), but not with glucose transporters (GLUT) 1 and 3, that are responsible for dehydroascorbic acid transport. In addition, AA pretreatment apparently lowered the conversion of MPTP to MPP+ in both brain areas in which the reduction in the ST was higher than in the SN. We postulated that this reduction in MPP+ was due to the scavenging effect of AA, and this was supported by the finding that AA reduced the production of MPP+ in cultured astrocytes. (Abstract shortened by UMI.)...