p53 inhibitors preserve dopamine neurons and motor function in experimental parkinsonism
p53 inhibitors preserve dopamine neurons and motor function in experimental parkinsonism
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DOI：
10.1002/ana.10350
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发表时间：
2002-11-01
影响因子：
11.2
通讯作者：
Mattson, MP
中科院分区：
文献类型：
--
作者：
Duan, WZ;Zhu, XX;Mattson, MP
目前用于帕金森氏症患者的药物可以暂时缓解症状，但不能阻止或减缓潜在的神经退行性疾病过程。越来越多的证据表明，帕金森氏病中的神经元通过一种称为细胞凋亡的过程死亡，这可能是由线粒体损伤和氧化应激引发的。我们报道了两种新的肿瘤抑制蛋白P53的合成抑制剂，PFT-α(PFT-α)和Z-1-117，在帕金森病小鼠模型中保护中脑多巴胺能神经元和改善行为结局方面非常有效。腹腔注射PFT-α或Z-1-117的小鼠在暴露于毒素1-甲基-4-苯基-1，2，3，6-四氢吡啶(MPTP)后，运动功能得到改善，对黑质纹状体多巴胺能神经元的损伤减少，多巴胺及其代谢产物的消耗减少。MPTP引起促凋亡蛋白Bax水平的增加，这可以通过给予小鼠PFT-α和Z-1-117来阻止。PFT-α和Z-1-117还可抑制MPP+所致培养的多巴胺能细胞Bax的生成和凋亡。我们的发现证明了P53在实验性帕金森病中的关键作用，并确定了一类具有临床潜力的新型合成P53抑制剂。
Drugs currently used for patients with Parkinson's disease provide temporary relief of symptoms but do not halt or slow the underlying neurodegenerative disease process. Increasing evidence suggests that neurons die in Parkinson's disease by a process called apoptosis, which may be triggered by mitochondrial impairment and oxidative stress. We report that two novel synthetic inhibitors of the tumor suppressor protein p53, pifithrin-alpha (PFT-alpha) and Z-1-117, are highly effective in protecting midbrain dopaminergic neurons and improving behavioral outcome in a mouse model of Parkinson's disease. Mice given intraperitoneal injections of PFT-alpha or Z-1-117 exhibited improved motor function, reduced damage to nigrostriatal dopaminergic neurons and reduced depletion of dopamine and its metabolites after exposure to the toxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). MPTP caused an increase in the level of the proapoptotic protein Bax, which was prevented by giving mice PFT-alpha and Z-1-117. PFT-alpha and Z-1-117 also suppressed Bax production and apoptosis in cultured dopaminergic cells exposed to MPP+. Our findings demonstrate a pivotal role for p53 in experimental parkinsonism and identify a novel class of synthetic p53 inhibitors with clinical potential.