Enhanced susceptibility to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine neurotoxicity in high-fat diet-induced obesity
Enhanced susceptibility to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine neurotoxicity in high-fat diet-induced obesity
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DOI：
10.1016/j.freeradbiomed.2004.12.008
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发表时间：
2005-03-15
影响因子：
7.4
通讯作者：
Kang, JH
中科院分区：
文献类型：
--
作者：
Choi, JY;Jang, EH;Kang, JH
目前，肥胖被认为是一种全身性炎症;然而，肥胖对多巴胺能神经元对氧化应激的脆弱性的影响尚未完全确定。我们评估了高脂饮食诱导的肥胖（HF DIO）对1-甲基-4-苯基-1，2，3，6-四氢吡啶（MPTP）治疗的小鼠神经毒性的影响。HF或匹配的正常饮食八周后，在接受亚毒性剂量MPTP（20 mg/kg）治疗的肥胖小鼠中观察到纹状体多巴胺和黑质微管相关蛋白2、锰超氧化物歧化酶和酪氨酸羟化酶水平严重下降。与匹配的瘦组相比。此外，MPTP可显著升高或抑制肥胖小鼠黑质中硝酸盐/亚硝酸盐和硫代巴比妥酸-丙二醛加合物的水平。有趣的是，MPTP治疗后，肥胖小鼠纹状体nNOS磷酸化和多巴胺周转率升高，但在瘦小鼠中未观察到。MPTP肥胖小鼠黑质氮应激反应的硝基酪氨酸免疫反应性高于对照组。在较高剂量的MPTP（60 mg/kg）下，肥胖小鼠的死亡率高于瘦小鼠。这些结果表明DIO可能通过增加活性氧和氮的水平增加多巴胺能神经元对MPTP的脆弱性，nNOS磷酸化在MPTP毒性和多巴胺稳态中的作用应进一步评估。(C)2004年爱思唯尔公司All rights reserved.
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. (C) 2004 Elsevier Inc. All rights reserved.