Department of Physiology, Shandong University School of Medicine, 44#, Wenhua Xi Road, Jinan, Shandong, 250012, P.R. China.
Neurobiol Dis. 2010 Aug;39(2):138-47. doi: 10.1016/j.nbd.2010.03.018. Epub 2010 Mar 30.
Mechanisms underlying delayed selective neuronal death after global cerebral ischemia remain to be clarified. Here, we report a critical role for tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) in the pathogenesis of cerebral ischemia. C57BL/6j mice were subjected to transient global brain ischemia. RT-PCR and immunohistochemistry showed that the expression of TRAIL and DR5 was upregulated following transient ischemia-reperfusion. Dual immunofluorescence analysis indicated that TRAIL expression was significantly more pronounced in astrocytes and activated microglia/macrophages, whereas DR5 expression was more pronounced in neurons, which had a good correlation with the distribution of apoptotic cells. Treatment with soluble DR5 reduced ischemic cell death after transient global ischemia through blocking the interaction of endogenous TRAIL with DR5. These results indicate that TRAIL plays a deleterious role in the pathogenesis of delayed neuronal damage after global cerebral ischemia and inhibition of TRAIL function in the brain may represent a novel neuroprotective strategy to treat ischemic stroke.
脑缺血后迟发性神经元选择性死亡的机制仍有待阐明。在这里，我们报告了肿瘤坏死因子（TNF）相关凋亡诱导配体（TRAIL）在脑缺血发病机制中的关键作用。C57BL/6j 小鼠经历短暂的全脑缺血。RT-PCR 和免疫组织化学显示，TRAIL 和 DR5 的表达在短暂的缺血再灌注后上调。双重免疫荧光分析表明，TRAIL 表达在星形胶质细胞和活化的小胶质细胞/巨噬细胞中更为明显，而 DR5 表达在神经元中更为明显，这与凋亡细胞的分布有很好的相关性。可溶性 DR5 治疗通过阻断内源性 TRAIL 与 DR5 的相互作用，减少短暂全脑缺血后的缺血性细胞死亡。这些结果表明，TRAIL 在全脑缺血后迟发性神经元损伤的发病机制中起有害作用，抑制脑内 TRAIL 功能可能代表治疗缺血性中风的一种新的神经保护策略。
