Institute for Drug Research, The Hebrew University of Jerusalem, Jerusalem, Israel.
Mol Med. 2011 May-Jun;17(5-6):448-56. doi: 10.2119/molmed.2011.00038. Epub 2011 Jan 25.
Histone deacetylase (HDAC) inhibitors are emerging as a novel class of potentially therapeutic agents for treating acute injuries of the central nervous system (CNS). In this review, we summarize data regarding the effects of HDAC inhibitor administration in models of acute CNS injury and discuss issues warranting clinical trials. We have previously shown that the pan-HDAC inhibitor ITF2357, a compound shown to be safe and effective in humans, improves functional recovery and attenuates tissue damage when administered as late as 24 h after injury. Using a well-characterized, clinically relevant mouse model of closed head injury, we demonstrated that a single dose of ITF2357 administered 24 h after injury improves neurobehavioral recovery and reduces tissue damage. ITF2357-induced functional improvement was found to be sustained up to 14 d after trauma and was associated with augmented histone acetylation. Single postinjury administration of ITF2357 also attenuated injury-induced inflammatory responses, as indicated by reduced glial accumulation and activation as well as enhanced caspase-3 expression within microglia/macrophages after treatment. Because no specific therapeutic intervention is currently available for treating brain trauma patients, the ability to affect functional outcome by postinjury administration of HDAC inhibitors within a clinically feasible timeframe may be of great importance. Furthermore, a growing body of evidence indicates that HDAC inhibitors are beneficial for treating various forms of acute CNS injury including ischemic and hemorrhagic stroke. Because HDAC inhibitors are currently approved for other use, they represent a promising new avenue of treatment, and their use in the setting of CNS injury warrants clinical evaluation.
组蛋白去乙酰化酶（HDAC）抑制剂作为一类新型的潜在治疗中枢神经系统（CNS）急性损伤的药物正在出现。在这篇综述中，我们总结了关于 HDAC 抑制剂在急性 CNS 损伤模型中给药的效果的数据，并讨论了值得临床试验的问题。我们之前已经表明，泛 HDAC 抑制剂 ITF2357 是一种在人类中被证明安全有效的化合物，当在损伤后 24 小时内给药时，可改善功能恢复并减轻组织损伤。使用一种经过良好特征描述的、具有临床相关性的小鼠闭合性颅脑损伤模型，我们证明了在损伤后 24 小时内给予单次剂量的 ITF2357 可改善神经行为恢复并减少组织损伤。发现 ITF2357 诱导的功能改善可持续至创伤后 14 天，并且与组蛋白乙酰化增加有关。在损伤后单次给予 ITF2357 还可减轻损伤引起的炎症反应，这表现为在治疗后小胶质细胞/巨噬细胞中胶质细胞积聚和激活减少以及 caspase-3 表达增强。由于目前尚无针对脑创伤患者的特定治疗干预措施，因此在临床可行的时间范围内通过损伤后给予 HDAC 抑制剂来影响功能结果可能非常重要。此外，越来越多的证据表明 HDAC 抑制剂对治疗各种形式的急性 CNS 损伤（包括缺血性和出血性中风）有益。由于 HDAC 抑制剂目前已获准用于其他用途，因此它们代表了一种很有前途的新治疗途径，并且它们在 CNS 损伤中的应用值得临床评估。
