Screening for inhibitors of the SOD1 gene promoter: pyrimethamine does not reduce SOD1 levels in cell and animal models.
Screening for inhibitors of the SOD1 gene promoter: pyrimethamine does not reduce SOD1 levels in cell and animal models.
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筛选 SOD1 基因启动子抑制剂：乙胺嘧啶不会降低细胞和动物模型中的 SOD1 水平。
DOI：
10.1016/j.neulet.2010.07.020
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发表时间：
2010
影响因子：
2.5
通讯作者：
BrownJr,RobertH
中科院分区：
文献类型：
--
作者：
Wright,PaulD;Huang,Mickey;Weiss,Alexandra;Matthews,Jonathan;Wightman,Nicholas;Glicksman,Marcie;BrownJr,RobertH
在20%的家族性和3%的散发性肌萎缩侧索硬化症（ALS）病例中检测到Cu/Zn超氧化物歧化酶（SOD 1）基因突变。尽管已知突变型SOD 1通过多种不良获得性功能诱导运动神经元死亡，但其确切的致病机制尚未明确。SOD 1毒性是剂量依赖性的;转基因小鼠中突变型SOD 1蛋白的水平决定疾病的易感性、发病和进展速度。因此，我们试图鉴定通过抑制SOD 1启动子来降低SOD 1水平的小分子。我们测试了乙胺嘧啶（以前报道抑制SOD 1表达），目前在人类和小鼠ALS试验中的几种化合物，以及一组1040种FDA批准的化合物。在基于PC 12细胞的测定中，没有化合物降低SOD 1启动子活性而没有伴随的细胞毒性。此外，乙胺嘧啶未能抑制HeLa细胞或野生型小鼠肝、脊髓和脑匀浆中的SOD 1蛋白水平。在人类和小鼠ALS试验中的34种化合物（包括利鲁唑、头孢曲松、米诺环素、PBA、锂、乙酰半胱氨酸）和另外一组1040种FDA批准的化合物也显示对SOD 1启动子活性没有影响。因此，本研究未能鉴定SOD 1基因表达的小分子抑制剂。
Mutations in the Cu/Zn superoxide dismutase (SOD1) gene are detected in 20% of familial and 3% of sporadic amyotrophic lateral sclerosis (ALS) cases. Although mutant SOD1 is known to induce motor neuron death via multiple adverse acquired functions, its exact pathogenic mechanism is not well defined. SOD1 toxicity is dose dependent; levels of mutant SOD1 protein in transgenic mice determine disease susceptibility, onset and rate of progression. We therefore sought to identify small molecules that reduce SOD1 levels by inhibiting the SOD1 promoter. We tested pyrimethamine (previously reported to suppress SOD1 expression), several compounds currently in trials in human and murine ALS, and a set of 1040 FDA-approved compounds. In a PC12 cell-based assay, no compounds reduced SOD1 promoter activity without concomitant cytotoxicity. Additionally, pyrimethamine failed to repress levels of SOD1 protein in HeLa cells or homogenates of liver, spinal cord and brain of wild-type mice. Thirty-four compounds (including riluzole, ceftriaxone, minocyclin, PBA, lithium, acetylcysteine) in human and mouse ALS trials and an additional set of 1040 FDA-approved compounds also showed no effect on SOD1 promoter activity. This present study thus failed to identify small molecule inhibitors of SOD1 gene expression.