Desole M S, Miele M, Esposito G, Fresu L G, Migheli R, Zangani D, Sircana S, Grella G, Miele E
Institute of Pharmacology, University of Sassari, Italy.
Pharmacol Biochem Behav. 1995 Aug;51(4):581-92. doi: 10.1016/0091-3057(94)00401-4.
Levels of ascorbic acid (AA), dehydroascorbic acid (DHAA), glutathione (GSH), uric acid, dopamine (DA), dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), 3-methoxytyramine (3-MT), noradrenaline (NA), 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), and 1-methyl-4-phenylpyridinium ion (MPP+) were determined in the striatum, striatal synaptosomes, and/or brain stem of 3- and 6-month-old male Wistar rats given MPTP 35-52 mg/kg IP. In older rats, MPTP 35 mg/kg caused a 38% death rate within 15 min-12 h. Levels of MPTP and MPP+ in the striatum, synaptosomes, and brain stem were directly correlated with the absolute MPTP dose/rat. MPTP decreased striatal DA metabolites and NA levels in the striatum and brain stem, and increased uric acid levels in all regions in all rats. All these changes were significantly correlated with MPP+ levels. GSH levels were increased in younger rats and decreased in older rats. AA oxidation was increased mainly in older rats. We conclude that acute lethality and regional brain MPTP and MPP+ levels depend upon the absolute dose of MPTP/rat rather than the relative dose/kg. In younger rats, the neuronal antioxidant GSH system is more efficient than in older rats, in which the response to MPP(+)-induced oxidative stress also involves AA oxidation. The increase in uric acid levels provides further evidence for a mechanism of MPTP neurotoxicity involving oxidative stress mediated by xanthine oxidase.
在腹腔注射35 - 52mg/kg MPTP的3月龄和6月龄雄性Wistar大鼠的纹状体、纹状体突触体和/或脑干中，测定了抗坏血酸（AA）、脱氢抗坏血酸（DHAA）、谷胱甘肽（GSH）、尿酸、多巴胺（DA）、二羟基苯乙酸（DOPAC）、高香草酸（HVA）、3 - 甲氧基酪胺（3 - MT）、去甲肾上腺素（NA）、1 - 甲基 - 4 - 苯基 - 1,2,3,6 - 四氢吡啶（MPTP）和1 - 甲基 - 4 - 苯基吡啶离子（MPP⁺）的水平。在老年大鼠中，35mg/kg的MPTP在15分钟至12小时内导致38%的死亡率。纹状体、突触体和脑干中MPTP和MPP⁺的水平与每只大鼠的MPTP绝对剂量直接相关。MPTP降低了纹状体中DA代谢产物以及纹状体和脑干中的NA水平，并使所有大鼠所有区域的尿酸水平升高。所有这些变化都与MPP⁺水平显著相关。GSH水平在年轻大鼠中升高，在老年大鼠中降低。AA氧化主要在老年大鼠中增加。我们得出结论，急性致死率以及区域脑内MPTP和MPP⁺水平取决于每只大鼠的MPTP绝对剂量，而非相对剂量/千克。在年轻大鼠中，神经元抗氧化GSH系统比老年大鼠更有效，在老年大鼠中，对MPP⁺诱导的氧化应激的反应还涉及AA氧化。尿酸水平的升高为MPTP神经毒性机制涉及由黄嘌呤氧化酶介导的氧化应激提供了进一步证据。
