Histone Deacetylase Inhibitors Preserve White Matter Structure and Function during Ischemia by Conserving ATP and Reducing Excitotoxicity
Histone Deacetylase Inhibitors Preserve White Matter Structure and Function during Ischemia by Conserving ATP and Reducing Excitotoxicity
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DOI：
10.1523/jneurosci.5379-10.2011
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发表时间：
2011-03-16
影响因子：
5.3
通讯作者：
Morrison, Richard S.
中科院分区：
文献类型：
--
作者：
Baltan, Selva;Murphy, Sean P.;Morrison, Richard S.
在实验动物模型中，白质（WM）损伤对卒中病理学的重要性被低估了，这可能导致了潜在治疗方法未能应用于卒中临床。组蛋白去乙酰化酶（HDAC）抑制剂具有神经保护作用，还能促进神经发生。这些特性使其成为卒中治疗的理想候选药物。在一条纯的白质束（分离的小鼠视神经）中，我们发现泛特异性和I类特异性HDAC抑制剂在氧糖剥夺（OGD）前后给药，可促进轴突的功能恢复并保护白质细胞结构。这种保护作用与星形胶质细胞谷氨酸转运体的上调、OGD期间谷氨酸积累的延迟和减少、轴突线粒体和少突胶质细胞的保存以及ATP水平的维持相关。有趣的是，HDAC 1、2和3的表达定位于星形胶质细胞，这表明神经胶质细胞基因转录和/或蛋白质乙酰化的变化可能对轴突起到保护作用。我们的研究结果表明，针对缺血性白质损伤中的线粒体能量调节和兴奋性毒性，使用HDAC抑制剂存在治疗机会。
The importance of white matter (WM) injury to stroke pathology has been underestimated in experimental animal models and this may have contributed to the failure to translate potential therapeutics into the stroke clinic. Histone deacetylase (HDAC) inhibitors are neuroprotective and also promote neurogenesis. These properties make them ideal candidates for stroke therapy. In a pure WM tract (isolated mouse optic nerve), we show that pan- and class I-specific HDAC inhibitors, administered before or after a period of oxygen and glucose deprivation (OGD), promote functional recovery of axons and preserve WM cellular architecture. This protection correlates with the upregulation of an astrocyte glutamate transporter, delayed and reduced glutamate accumulation during OGD, preservation of axonal mitochondria and oligodendrocytes, and maintenance of ATP levels. Interestingly, the expression of HDACs 1, 2, and 3 is localized to astrocytes, suggesting that changes in glial cell gene transcription and/or protein acetylation may confer protection to axons. Our findings suggest that a therapeutic opportunity exists for the use of HDAC inhibitors, targeting mitochondrial energy regulation and excitotoxicity in ischemic WM injury.