Langley Brett, Brochier Camille, Rivieccio Mark A
Burke/Cornell Medical Research Institute, 785 Mamaroneck Road, White Plains, NY 10605, USA.
Stroke. 2009 Aug;40(8):2899-905. doi: 10.1161/STROKEAHA.108.540229. Epub 2009 May 28.
Achieving therapeutic efficacy in ischemic stroke represents one of the biggest challenges in translational neurobiology. Despite extensive efforts, tissue plasminogen activator remains the only available intervention for enhancing functional recovery in humans once a stroke has occurred. To expand the repertoire of therapeutic options in stroke, one must consider and target its diverse pathophysiologies that trigger cell loss in a manner that also permits and enhances neuronal plasticity and repair. Several converging lines of inquiry suggest that histone deacetylase (HDAC) inhibition could be a strategy to achieve these goals. Here, we review evidence that targeting HDACs with low-molecular-weight inhibitors significantly decreases neuronal injury and improves functional outcome in multiple preclinical models of focal ischemia. These salutary effects emanate, in part, from modifications of chromatin and nonchromatin proteins that enhance adaptive gene expression or adaptive protein function. Together, the findings suggest that HDAC inhibition is a strategy capable of targeting diverse pathophysiologies of stroke with a wide therapeutic window.
在缺血性中风中实现治疗效果是转化神经生物学面临的最大挑战之一。尽管付出了巨大努力，但组织型纤溶酶原激活剂仍然是中风发生后人类增强功能恢复的唯一可用干预措施。为了扩大中风治疗选择的范围，必须考虑并针对其多种病理生理学，这些病理生理学以允许并增强神经元可塑性和修复的方式引发细胞损失。几条相互汇聚的研究线索表明，抑制组蛋白脱乙酰酶（HDAC）可能是实现这些目标的一种策略。在此，我们综述了证据，即使用低分子量抑制剂靶向HDAC可在多种局灶性缺血临床前模型中显著减少神经元损伤并改善功能结局。这些有益作用部分源于染色质和非染色质蛋白的修饰，这些修饰增强了适应性基因表达或适应性蛋白功能。总之，这些发现表明HDAC抑制是一种能够以广泛的治疗窗口靶向中风多种病理生理学的策略。
