Essential Role for Zinc-Triggered p75NTR Activation in Preconditioning Neuroprotection
Essential Role for Zinc-Triggered p75NTR Activation in Preconditioning Neuroprotection
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DOI：
10.1523/jneurosci.3421-08.2008
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发表时间：
2008-10-22
影响因子：
5.3
通讯作者：
Kim, Yang-Hee
中科院分区：
文献类型：
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作者：
Lee, Jin-Yeon;Kim, Yu-Jin;Kim, Yang-Hee
脑缺血预处理（PC）是一种现象，通过轻微的缺血损伤使神经元抵抗随后的强损伤。脑缺血PC的关键步骤包括caspase-3激活和聚（adp -核糖）聚合酶-1 （PARP-1）裂解，但上游事件尚未明确阐明。我们测试了内源性锌对大鼠脑缺血PC是否有必要。局部缺血PC后，部分神经元出现轻度、短暂的锌积累。此外，在缺血性PC期间，CaEDTA脑室内给药消除了锌的积累和对随后的完全缺血的保护作用。为了阐明锌触发PC （Zn PC）效应的机制，皮质培养物暴露于亚致死水平的锌，18 h后暴露于致死水平的锌或NMDA。Zn PC表现出缺血PC的特征，包括caspase-3激活、PARP-1裂解和HSP70诱导，这些都是随后对NMDA或锌毒性的神经保护至关重要。HSP70的诱导是保护所必需的，因为它在细胞凋亡前阻止了caspase-3的激活。有趣的是，在体外Zn - PC和体内缺血性PC中，p75（NTR）都是神经保护所必需的。这些结果表明，缺血PC期间caspase-3的激活是随后神经保护的必要事件，可能是由轻度锌积累和随之而来的神经元p75（NTR）激活引起的。
Ischemic preconditioning (PC) of the brain is a phenomenon by which mild ischemic insults render neurons resistant to subsequent strong insults. Key steps in ischemic PC of the brain include caspase-3 activation and poly(ADP-ribose) polymerase-1 (PARP-1) cleavage, but upstream events have not been clearly elucidated. We have tested whether endogenous zinc is required for ischemic PC of the brain in rats. Mild, transient zinc accumulation was observed in certain neurons after ischemic PC. Moreover, intraventricular administration of CaEDTA during ischemic PC abrogated both zinc accumulation and the protective effect against subsequent full ischemia. To elucidate the mechanism of the zinc-triggered PC (Zn PC) effect, cortical cultures were exposed to sublethal levels of zinc, and 18 h later to lethal levels of zinc or NMDA. Zn PC exhibited the characteristic features of ischemic PC, including caspase-3 activation, PARP-1 cleavage, and HSP70 induction, all of which are crucial for subsequent neuroprotection against NMDA or zinc toxicity. HSP70 induction was necessary for protection, as it halted caspase-3 activation before apoptosis. Interestingly, in both Zn PC in vitro and ischemic PC in vivo, p75(NTR) was necessary for neuroprotection. These results suggest that caspase-3 activation during ischemic PC, a necessary event for subsequent neuroprotection, may result from mild zinc accumulation and the consequent p75(NTR) activation in neurons.