Additive neuroprotective effects of a histone deacetylase inhibitor and a catalytic antioxidant in a transgenic mouse model of amyotrophic lateral sclerosis
Additive neuroprotective effects of a histone deacetylase inhibitor and a catalytic antioxidant in a transgenic mouse model of amyotrophic lateral sclerosis
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DOI：
10.1016/j.nbd.2005.09.013
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发表时间：
2006-04-01
影响因子：
6.1
通讯作者：
Beal, MF
中科院分区：
文献类型：
--
作者：
Petri, S;Kiaei, M;Beal, MF
肌萎缩侧索硬化症是一种毁灭性的神经退行性疾病，目前还没有有效的治疗方法。其发病机制涉及多个分子机制。我们在G93A转基因小鼠模型中检测了催化抗氧化剂AEOL 10150、组蛋白去乙酰酶抑制剂苯丁酸酯以及PBA和AEOL 10150的组合。仅AEOL 10150一项就可改善运动功能并延长11%的存活期，单用PBA可显著改善运动功能并延长存活期。13%。PBA和AEOL 10150合计可使存活率提高19%。Western印迹结果证实组蛋白乙酰化增强。实时定量RT-PCR分析显示，能够保护细胞免受氧化应激和细胞凋亡的化合物表达上调。与给药相比，腰髓氧化损伤的标记物减少了。这些结果表明，抑制细胞凋亡和阻断氧化应激的药物在治疗突变SOD1相关的ALS方面显示出有效性，针对不同疾病机制的药物组合可能发挥相加的治疗作用。(C)2005 Elsevier Inc.保留所有权利。
ALS is a devastating neurodegenerative disorder for which no effective treatment exists. Multiple molecular mechanisms are involved in the pathogenesis. We tested the catalytic antioxidant AEOL 10150, the histone deacetylase inhibitor phenylbutyrate (PBA), and the combination of PBA and AEOL 10150 in the G93A transgenic mouse model, administered from disease onset. AEOL 10150 alone improved motor function and extended survival by 11%, PBA alone significantly improved motor function and extended survival by. 13%. PBA and AEOL 10150 together increased survival by 19%. Increased histone acetylation was confirmed by Western blot. Quantitative real-time RTPCR analysis revealed upregulation of compounds capable of protecting cells against oxidative stress and apoptosis. Markers of oxidative damage were reduced in the lumbar spinal cord as compared to vehicle administration. These results suggest that agents inhibiting apoptosis and blocking oxidative stress show efficacy in treating mutant-SOD1-associated ALS and that a combination of agents targeting different disease mechanisms may exert additive therapeutic effects. (c) 2005 Elsevier Inc. All rights reserved.