Tissue-type plasminogen activator has a neuroprotective effect in the ischemic brain mediated by neuronal TNF-α
Tissue-type plasminogen activator has a neuroprotective effect in the ischemic brain mediated by neuronal TNF-α
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DOI：
10.1038/jcbfm.2011.106
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发表时间：
2012-01-01
影响因子：
6.3
通讯作者：
Yepes, Manuel
中科院分区：
文献类型：
--
作者：
Haile, Woldeab B.;Wu, Jialing;Yepes, Manuel
大脑皮层神经元对缺氧具有高度敏感性，它们的存活取决于它们适应环境中氧浓度变化的能力。组织型纤溶酶原激活剂（tPA）是一种丝氨酸蛋白酶，其将酶原纤溶酶原激活成纤溶酶。缺氧诱导大脑皮层神经元释放tPA，并且已经提出tPA介导缺氧和缺血性神经元死亡。在这里，我们表明，tPA是没有神经毒性作用，而是一种内源性神经保护剂，使神经元耐致命的缺氧和缺血的影响。我们目前在体外和体内的证据表明，内源性tPA和重组tPA诱导神经元肿瘤坏死因子-α的表达。这种作用由纤溶酶和N-甲基-D-天冬氨酸受体介导，导致细胞周期蛋白依赖性激酶抑制剂p21的表达增加和p21介导的早期缺氧和缺血耐受的发展。脑血流与代谢杂志（2012）32，57 - 69; doi：10.1038/jcbfm.2011.106; 2011年7月27日在线发表
Cerebral cortical neurons have a heightened sensitivity to hypoxia and their survival depends on their ability to accommodate to changes in the concentration of oxygen in their environment. Tissue-type plasminogen activator (tPA) is a serine proteinase that activates the zymogen plasminogen into plasmin. Hypoxia induces the release of tPA from cerebral cortical neurons, and it has been proposed that tPA mediates hypoxic and ischemic neuronal death. Here, we show that tPA is devoid of neurotoxic effects and instead is an endogenous neuroprotectant that renders neurons resistant to the effects of lethal hypoxia and ischemia. We present in vitro and in vivo evidence indicating that endogenous tPA and recombinant tPA induce the expression of neuronal tumor necrosis factor-alpha. This effect, mediated by plasmin and the N-methyl-D-aspartate receptor, leads to increased expression of the cyclin-dependent kinase inhibitor p21 and p21-mediated development of early hypoxic and ischemic tolerance. Journal of Cerebral Blood Flow & Metabolism (2012) 32, 57-69; doi:10.1038/jcbfm.2011.106; published online 27 July 2011