Anesthesia-induced developmental neurodegeneration

描述（由申请人提供）：这是R 01授权# HD 044517竞争性更新的重新提交。这些实验是早期实验的延伸，旨在破译麻醉诱导的发育性神经退行性变的细胞通路。除了在脆弱的大脑区域引起广泛的凋亡性神经变性外，在大脑生长高峰期全身麻醉暴露还会导致以后生活中的学习和记忆缺陷。对照组和麻醉组动物在学习能力上的差距在成年期逐渐扩大.此外，回顾性临床证据表明，非常年幼的儿童暴露于全身麻醉和随后的终身学习障碍之间存在关系。由于全身麻醉无法避免，因此更好地了解麻醉诱导的发育性神经退行性变的关键机制以及改善方法对公共卫生至关重要。我们的体内啮齿动物研究表明，激活的内在（神经元依赖性）凋亡途径是神经元损伤的最早预警信号。在最初的几个小时内，全身麻醉会导致bcl-XL蛋白水平的显著下降，随后线粒体释放的细胞色素-c大量增加。这导致半胱天冬酶-9和-3的激活、DNA片段化和神经元死亡。此外，我们最近的体内研究表明，全身麻醉诱导活性氧的显着上调和发育中的未成熟神经元线粒体的形态和功能损伤。治疗干预，旨在清除过量的活性氧自由基使用EUK-134，合成的超氧化物歧化酶和过氧化氢酶模拟物，废除麻醉诱导的学习障碍，并显着改善麻醉诱导的活性氧自由基的增加。麻醉诱导的活性氧上调和发育中神经元线粒体损伤的确切机制必须确定，以便设计治疗干预措施。这是我们修改后的应用程序的主要重点。 公共卫生相关性：临床使用的全身麻醉剂对发育中的哺乳动物大脑有损害。由于全身麻醉药是一个必要的，往往无法避免，更好地了解麻醉诱导的发育神经毒性的关键机制和改善其影响的方法是非常重要的。利用体内和体外系统，本研究旨在探讨发育性突触发生过程中麻醉诱导的活性氧介导的神经退行性变的机制。

DESCRIPTION (provided by applicant): This is a resubmission of a competitive renewal of the R01 grant # HD 044517. The proposed experiments are extensions of earlier ones aimed at deciphering the cellular pathways responsible for anesthesia- induced developmental neurodegeneration. In addition to causing widespread apoptotic neurodegeneration in vulnerable brain regions, general anesthesia exposure at the peak of the brain growth spurt causes learning and memory deficiencies later in life. The gap in learning abilities between control and anesthesia- treated animals progressively widens in adulthood. Moreover, retrospective clinical evidence suggests that there is a relationship between the exposure of very young children to general anesthesia and subsequent life-long learning disabilities. Since general anesthesia cannot be avoided, better understanding the key mechanisms of anesthesia-induced developmental neurodegeneration and ways to ameliorate it are critically important to public health. Our in-vivo rodent studies have suggested that activation of the intrinsic (mitochondria-dependent) apoptotic pathway is the earliest warning sign of neuronal damage. Within the very first couple of hours, general anesthesia causes significant decrease in protein levels of bcl-XL which is quickly followed by a massive increase in cytochrome-c release from mitochondria. This leads to activation of caspase-9, and -3, DNA fragmentation, and neuronal death. In addition, our most recent in-vivo studies demonstrate that general anesthesia induces significant up-regulation of reactive oxygen species and both morphological and functional impairment of developing mitochondria in the immature neurons. Therapeutic intervention aimed at scavenging excessive reactive oxygen species using EUK-134, a synthetic superoxide dismutase and catalase mimetic, abolished anesthesia-induced learning impairment and significantly ameliorated anesthesia-induced increases in reactive oxygen species. The exact mechanisms operational in anesthesia-induced up-regulation of reactive oxygen species and mitochondria damage in the developing neurons must be determined so that therapeutic interventions can be devised. This is the main focus of our revised application. PUBLIC HEALTH RELEVANCE: Clinically used general anesthetics are damaging to developing mammalian brain. Since general anesthetics are a necessity that often cannot be avoided, better understanding of the key mechanisms of anesthesia-induced developmental neurotoxicity and ways to ameliorate their effects are of great importance. Using in-vivo and ex-vitro systems, this proposal aims to investigate the mechanisms involved in anesthesia-induced reactive oxygen-mediated neurodegeneration during developmental synaptogenesis.