A synthetic inhibitor of p53 protects neurons against death induced by ischemic and excitotoxic insults, and amyloid β-peptide
A synthetic inhibitor of p53 protects neurons against death induced by ischemic and excitotoxic insults, and amyloid β-peptide
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DOI：
10.1046/j.1471-4159.2001.00220.x
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发表时间：
2001-04-01
影响因子：
4.7
通讯作者：
Mattson, MP
中科院分区：
文献类型：
--
作者：
Culmsee, C;Zhu, XX;Mattson, MP
肿瘤抑制蛋白p53在几个实验环境中对神经元死亡是必需的，并且可能参与人类神经退行性疾病。基于最近在癌症治疗领域的临床前研究中表征p53的化学抑制剂的研究，我们合成了化合物pifithrin-alpha，并在与中风和神经退行性疾病的发病机制相关的实验模型中评估了其潜在的神经保护特性。匹非他林-α保护神经元免于由DNA损伤剂、淀粉样蛋白β-肽和谷氨酸诱导的细胞凋亡。匹非他林-α的保护与p53 DNA结合活性降低、p53靶基因Bax表达降低以及线粒体功能障碍和半胱天冬酶激活的抑制相关。给予pifithrin-alpha的小鼠表现出皮质和纹状体神经元对局灶性缺血损伤的抵抗力增加，海马神经元对兴奋性毒性损伤的抵抗力增加。这些临床前研究证明了p53抑制剂在中风和神经退行性疾病模型中的功效，并表明抑制p53的药物可以降低相关人类神经退行性疾病中脑损伤的程度。
The tumor suppressor protein p53 is essential for neuronal death in several experimental settings and may participate in human neurodegenerative disorders. Based upon recent studies characterizing chemical inhibitors of p53 in preclinical studies in the cancer therapy field, we synthesized the compound pifithrin-alpha and evaluated its potential neuroprotective properties in experimental models relevant to the pathogenesis of stroke and neurodegenerative disorders. Pifithrin-alpha protected neurons against apoptosis induced by DNA-damaging agents, amyloid beta -peptide and glutamate, Protection by pifithrin-alpha was correlated with decreased p53 DNA-binding activity, decreased expression of the p53 target gene Bax and suppression of mitochondrial dysfunction and caspase activation. Mice given pifithrin-alpha exhibited increased resistance of cortical and striatal neurons to focal ischemic injury and of hippocampal neurons to excitotoxic damage. These preclinical studies demonstrate the efficacy of a p53 inhibitor in models of stroke and neurodegenerative disorders, and suggest that drugs that inhibit p53 may reduce the extent of brain damage in related human neurodegenerative conditions.