Identification and characterization of cholest-4-en-3-one, oxime (TRO19622), a novel drug candidate for amyotrophic lateral sclerosis
Identification and characterization of cholest-4-en-3-one, oxime (TRO19622), a novel drug candidate for amyotrophic lateral sclerosis
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DOI：
10.1124/jpet.107.123000
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发表时间：
2007-08-01
影响因子：
3.5
通讯作者：
Pruss, Rebecca M.
中科院分区：
文献类型：
--
作者：
Bordet, Thierry;Buisson, Bruno;Pruss, Rebecca M.
肌萎缩侧索硬化症（ALS）是一种致命的神经退行性疾病，其特征是皮质和脊髓运动神经元的进行性死亡，目前尚无有效的治疗方法。利用基于细胞的检测方法，研究人员筛选了大约40,000种低分子量化合物，以确定潜在的小分子治疗方法。我们报道鉴定出胆-4-烯-3-酮肟（TRO19622）作为治疗ALS的潜在候选药物。在体外实验中，TRO19622以剂量依赖的方式促进了缺乏营养支持的运动神经元的存活。在体内实验中，TRO19622可使新生大鼠的运动神经元免于axotomy诱导的细胞死亡，并促进小鼠坐骨神经挤压后的神经再生。在SOD1（G93A）转基因小鼠（一种家族性ALS模型）中，TRO19622治疗改善了运动表现，延缓了临床疾病的发作，延长了生存期。TRO19622直接与线粒体通透性过渡孔的两个组成部分结合：电压依赖性阴离子通道和转运蛋白18kda（或外周苯二氮卓受体），提示其神经保护活性的潜在机制。TRO19622可能对ALS和其他运动神经元和神经退行性疾病具有治疗潜力。
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by progressive death of cortical and spinal motor neurons, for which there is no effective treatment. Using a cell-based assay for compounds capable of preventing motor neuron cell death in vitro, a collection of approximately 40,000 low-molecular-weight compounds was screened to identify potential small-molecule therapeutics. We report the identification of cholest-4-en-3-one, oxime (TRO19622) as a potential drug candidate for the treatment of ALS. In vitro, TRO19622 promoted motor neuron survival in the absence of trophic support in a dose-dependent manner. In vivo, TRO19622 rescued motor neurons from axotomy-induced cell death in neonatal rats and promoted nerve regeneration following sciatic nerve crush in mice. In SOD1(G93A) transgenic mice, a model of familial ALS, TRO19622 treatment improved motor performance, delayed the onset of the clinical disease, and extended survival. TRO19622 bound directly to two components of the mitochondrial permeability transition pore: the voltage-dependent anion channel and the translocator protein 18 kDa (or peripheral benzodiazepine receptor), suggesting a potential mechanism for its neuroprotective activity. TRO19622 may have therapeutic potential for ALS and other motor neuron and neurodegenerative diseases.