Upregulation of mitochondrial base-excision repair capability within rat brain after brief ischemia
Upregulation of mitochondrial base-excision repair capability within rat brain after brief ischemia
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DOI：
10.1097/01.wcb.0000039286.37737.19
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发表时间：
2003-01-01
影响因子：
6.3
通讯作者：
Simon, RP
中科院分区：
文献类型：
--
作者：
Chen, DX;Minami, M;Simon, RP
脑缺血短暂发作对随后的长时间缺血挑战赋予保护（耐受性）的机制尚不清楚，但可能涉及细胞损伤修复能力的上调。线粒体是调控细胞死亡途径的关键位点，线粒体基因的损伤与许多神经系统疾病和衰老有关。因此，作者检测了DNA碱基切除修复（BER）途径在短暂（诱导耐受性）或长时间（产生损伤）局灶性脑缺血后对大鼠脑线粒体的反应。短暂（30分钟）大脑中动脉闭塞（MCAO）诱导轻度线粒体DNA氧化损伤，并启动延长（长达72小时）的激活，高于线粒体BER途径主要酶的控制水平，包括尿嘧啶DNA糖基化酶，无尿嘧啶/无嘧啶（AP）核酸内切酶，DNA聚合酶和DNA连接酶。相比之下，长时间（100分钟MCAO）缺血引起更严重的线粒体氧化DNA损伤，而BER活性的升高是短暂的（类似于1小时），在4至72小时的过程中下降到低于对照水平。这些数据揭示了短时间缺血和长时间缺血后脑容量的差异，这可能有助于神经元抵抗随后的缺血损伤的能力。
The mechanism by which brief episodes of cerebral ischemia confer protection (tolerance) against subsequent prolonged ischemic challenges remains unclear, but may involve upregulation of cell injury repair capability. The mitochondrion is a key site for the regulation of cell death pathways, and damage to mitochondrial genes has been linked to a number of neurologic diseases and aging. Therefore, the authors examined the response of the DNA base excision repair (BER) pathway in rat brain mitochondria after either brief (tolerance-inducing) or prolonged (injury-producing) focal cerebral ischemia Brief (30-minute) middle cerebral artery occlusion (MCAO) induced mild oxidative mitochondrial DNA damage and initiated a prolonged (up to 72-hour) activation above control levels of the principal enzymes of the mitochondrial BER pathway, including uracil DNA glycosylase, apurinic/apyrimidinic (AP) endonuclease, DNA polymerase-gamma, and DNA ligase. In contrast, prolonged (100-minute MCAO) ischemia induced more substantial mitochondrial oxidative DNA damage whereas elevation of BER activity was transient (similar to1 hour), declining to less than control levels over the course of 4 to 72 hours. These data reveal the differences in BER capacity after brief or prolonged ischemia, which may contribute to the neuron's ability to resist subsequent ischemic insults.