Ischemic preconditioning in the rat brain enhances the repair of endogenous oxidative DNA damage by activating the base-excision repair pathway
Ischemic preconditioning in the rat brain enhances the repair of endogenous oxidative DNA damage by activating the base-excision repair pathway
复制标题
DOI：
10.1038/sj.jcbfm.9600180
复制
发表时间：
2006-02-01
影响因子：
6.3
通讯作者：
Chen, J
中科院分区：
文献类型：
--
作者：
Li, WJ;Luo, YM;Chen, J
大脑缺血耐受性的发展，即短暂的亚致死“预处理”缺血可减轻随后严重缺血造成的损伤，可能涉及促进神经元存活的多种细胞内信号传导事件的激活。在这项研究中，在由三次缺血预适应（IP）产生的缺血耐受大鼠模型中研究了诱导性 DNA 碱基切除修复（BER）的潜在作用，BER 是一种内源性适应性反应，可防止氧化 DNA 损伤的有害影响。这种 IP 范例在 2 小时大脑中动脉闭塞 (MCAO) 前 2 天和 5 天应用时，72 小时后显着减少了额顶叶皮层的梗塞体积。与这种保护作用相关的是，在 2 小时 MCAO 后，IP 显着减弱了几种氧化 DNA 损伤的核积累，包括 8-oxodG、AP 位点和 DNA 链断裂。因此，在预处理大脑的缺血再灌注过程中，有害的 DNA 损伤反应事件（包括 NAD 消耗和 p53 激活）减少。然后通过测量核提取物中的 BER 活性来研究预处理大脑中 DNA 损伤减少的机制。 IP后β-聚合酶介导的BER活性显着增加，并且这种激活发生在缺血耐受之前（24小时）和缺血耐受过程中（48至72小时）。类似地，IP 后 AP 位点和 8-oxodG 切口的活性也上调。 IP 后 BER 活性上调可能是由于修复酶 β-聚合酶、AP 核酸内切酶和 OGG1 表达增加所致。这些结果表明，BER 通路的激活可能通过增强缺血性损伤后内源性氧化 DNA 损伤的修复来促进 IP 诱导的神经保护。
The development of ischemic tolerance in the brain, whereby a brief period of sublethal 'preconditioning' ischemia attenuates injury from subsequent severe ischemia, may involve the activation of multiple intracellular signaling events that promote neuronal survival. In this study, the potential role of inducible DNA base-excision repair (BER), an endogenous adaptive response that prevents the detrimental effect of oxidative DNA damage, has been studied in the rat model of ischemic tolerance produced by three episodes of ischemic preconditioning (IP). This paradigm of IP, when applied 2 and 5 days before 2-h middle cerebral artery occlusion (MCAO), significantly decreased infarct volume in the frontal-parietal cortex 72 h later. Correlated with this protective effect, IP markedly attenuated the nuclear accumulations of several oxidative DNA lesions, including 8-oxodG, AP sites, and DNA strand breaks, after 2-h MCAO. Consequently, harmful DNA damage-responsive events, including NAD depletion and p53 activation, were reduced during postischemic reperfusion in preconditioned brains. The mechanism underlying the decreased DNA damage in preconditioned brain was then investigated by measuring BER activities in nuclear extracts. Beta-polymerase-mediated BER activity was markedly increased after IP, and this activation occurred before ( 24 h) and during the course of ischemic tolerance ( 48 to 72 h). In similar patterns, the activities for AP site and 8-oxodG incisions were also upregulated after IP. The upregulation of BER activities after IP was likely because of increased expression of repair enzymes beta-polymerase, AP endonuclease, and OGG1. These results suggest that the activation of the BER pathway may contribute to IP-induced neuroprotection by enhancing the repair of endogenous oxidative DNA damage after ischemic injury.