Suberoylanilide hydroxamic acid, a histone deacetylase inhibitor, protects dopaminergic neurons from neurotoxin-induced damage
Suberoylanilide hydroxamic acid, a histone deacetylase inhibitor, protects dopaminergic neurons from neurotoxin-induced damage
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DOI：
10.1111/j.1476-5381.2011.01575.x
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发表时间：
2012-01-01
影响因子：
7.3
通讯作者：
Lu, R. B.
中科院分区：
文献类型：
--
作者：
Chen, S. H.;Wu, H. M.;Lu, R. B.
背景和目的预防或改变疾病的疗法对于阿尔茨海默病、帕金森病和亨廷顿病等神经退行性疾病的治疗至关重要。然而，目前还没有这样的干预措施。越来越多的证据表明，在实验模型中，给予组蛋白脱乙酰酶(HDAC)抑制剂可以改善广泛的神经和精神障碍。琥珀酰苯胺异羟肟酸(SAHA)是美国食品和药物管理局批准的第一种仅用于癌症治疗的HDAC抑制剂。本研究旨在探索SAHA在体外帕金森病模型中治疗神经退行性疾病的潜在新适应症。本研究采用体外中脑神经元胶质细胞培养和重组培养方法，研究SAHA的神经营养和神经保护作用。我们用多巴胺摄取法测定了多巴胺能神经元的毒性，用酶联免疫吸附试验和实时荧光定量RT-PCR法对神经营养物质进行了形态分析和表达。结果在培养的中脑神经元神经胶质细胞中，SAHA呈剂量和时间依赖性地延长存活时间，并对神经毒素诱导的多巴胺能神经元死亡具有保护作用。机制研究表明，SAHA的神经保护作用部分是通过抑制组蛋白去乙酰化促进神经营养因子从星形胶质细胞释放出来的。结论和应用本研究证实了SAHA新的神经营养和神经保护作用，提示进一步研究这种HDAC抑制剂可为神经退行性疾病的治疗提供新的治疗途径。
BACKGROUND AND PURPOSEPrevention or disease-modifying therapies are critical for the treatment of neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease and Huntington's disease. However, no such intervention is currently available. Growing evidence has demonstrated that administration of histone deacetylase (HDAC) inhibitors ameliorates a wide range of neurologic and psychiatric disorders in experimental models. Suberoylanilide hydroxamic acid (SAHA) was the first HDAC inhibitor approved by the Food and Drug Administration for the sole use of cancer therapy. The purpose of this study was to explore the potential new indications of SAHA for therapy of neurodegenerative diseases in in vitro Parkinson's disease models.EXPERIMENTAL APPROACHMesencephalic neuron glia cultures and reconstituted cultures were used to investigate neurotrophic and neuroprotective effects of SAHA. We measured toxicity in dopaminergic neurons, using dopamine uptake assay and morphological analysis and expression of neurotrophic substances by enzyme-linked immunosorbent assay and real-time RT PCR.KEY RESULTSIn mesencephalic neuron glia cultures, SAHA displayed dose- and time-dependent prolongation of the survival and protection against neurotoxin-induced neuronal death of dopaminergic neurons. Mechanistic studies revealed that the neuroprotective effects of SAHA were mediated in part by promoting release of neurotrophic factors from astroglia through inhibition of histone deacetylation.CONCLUSION AND IMPLICATIONSThe novel neurotrophic and neuroprotective effects of SAHA demonstrated in this study suggest that further study of this HDAC inhibitor could provide a new therapeutic approach to the treatment of neurodegenerative diseases.