Enhanced susceptibility to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine neurotoxicity in high-fat diet-induced obesity.
Currently, obesity is considered a systemic inflammation; however, the effects of obesity on the vulnerability of dopaminergic neurons to 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 the levels of striatal dopamine and of nigral microtubule-associated protein 2, manganese superoxide dismutase, and tyrosine hydroxylase was observed in obese mice treated with subtoxic doses of MPTP (20 mg/kg) compared with the matched lean group. In addition, the levels of nitrate/nitrite and thiobarbituric acid-malondialdehyde adducts in the substantia nigra of obese mice were reciprocally elevated or suppressed by MPTP. Interestingly, striatal nNOS phosphorylation and dopamine turnover were elevated in obese mice after MPTP treatment, but were 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 in 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 role of nNOS phosphorylation in the MPTP toxicities and dopamine homeostasis should be further evaluated.
Choi
Ji-Young
JY
Department of Pharmacology, Medicinal Toxicology Research Center, CDIR, Inha University, Incheon 400-712, South Korea.
Jang
Eun-Hee
EH
Park
Chang-Shin
CS
Kang
Ju-Hee
JH
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000378:metabolism*; D000821:Animal Feed; D000818:Animals; D000975:Antioxidants / Q000378:metabolism / Q000494:pharmacology; D001253:Astrocytes / Q000378:metabolism; D015153:Blotting, Western; D001835:Body Weight; D002851:Chromatography, High Pressure Liquid; D004041:Dietary Fats / Q000378:metabolism*; D004198:Disease Susceptibility; D004298:Dopamine / Q000378:metabolism; D015259:Dopamine Agents / Q000633:toxicity; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D015151:Immunoblotting; D007150:Immunohistochemistry; D015227:Lipid Peroxidation; D020267:MPTP Poisoning / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D020258:Neurotoxicity Syndromes / Q000209:etiology; D009566:Nitrates / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D009573:Nitrites / Q000378:metabolism; D009765:Obesity / Q000378:metabolism / Q000473:pathology*; D018384:Oxidative Stress; D010766:Phosphorylation; D013378:Substantia Nigra / Q000378:metabolism; D013482:Superoxide Dismutase / Q000378:metabolism; D017392:Thiobarbituric Acid Reactive Substances; D013997:Time Factors; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000378:metabolism
D000975:Antioxidants; D004041:Dietary Fats; D015259:Dopamine Agents; D005904:Glial Fibrillary Acidic Protein; D009566:Nitrates; D009573:Nitrites; D017392:Thiobarbituric Acid Reactive Substances; D009569:Nitric Oxide; C002744:3-nitrotyrosine; D014443:Tyrosine; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D013482:Superoxide Dismutase; D004298:Dopamine