Anesthesia-induced developmental neurodegeneration

描述（由申请人提供）：这是R01拨款# HD 044517的竞争性续期的重新提交。提出的实验是早期实验的延伸，旨在破译麻醉诱导的发育性神经变性的细胞通路。除了在脆弱的大脑区域引起广泛的凋亡性神经变性外，在大脑生长高峰期接受全身麻醉还会导致以后的学习和记忆缺陷。在成年期，对照组和麻醉组之间的学习能力差距逐渐扩大。此外，回顾性临床证据表明，非常年幼的儿童接受全身麻醉与随后的终身学习障碍之间存在关系。由于全身麻醉不可避免，因此更好地了解麻醉诱导的发育性神经变性的关键机制和改善方法对公共卫生至关重要。我们在啮齿动物体内的研究表明，内在（线粒体依赖）凋亡途径的激活是神经元损伤的最早警告信号。在最初的几个小时内，全身麻醉导致bcl-XL蛋白水平显著下降，随后线粒体释放的细胞色素c大量增加。这导致caspase-9和-3的激活，DNA断裂和神经元死亡。此外，我们最近的体内研究表明，全身麻醉诱导活性氧的显著上调以及未成熟神经元中发育中的线粒体的形态和功能损伤。使用EUK-134（一种合成的超氧化物歧化酶和过氧化氢酶模拟物）清除过量活性氧的治疗干预，消除了麻醉诱导的学习障碍，并显著改善了麻醉诱导的活性氧增加。必须确定麻醉诱导的活性氧上调和发育中的神经元线粒体损伤的确切机制，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焦点。

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.