Anesthetic-Induced Neurotoxicity: Molecular Pathways and Genetic Risk Factors

一些接受麻醉和手术的人会经历麻醉剂引起的神经毒性(Ain)。 可归因于挥发性全身麻醉剂(VGA)。暴露于VGA后的AIN可呈现不同的 表型，包括急性神经变性，神志不清，儿童终身认知障碍和 老年人神经退行性变加速甚至新发。尽管有争议的临床试验，FDA在 对最近的数据做出了深远的回应，对孕妇使用VGA发出了警告，并 年幼的孩子。此外，美国麻醉学家协会的围手术期大脑健康倡议 提高了人们对老年人大脑AIN的认识。因为无论是AIN的病理生理学还是其危险因素都不是 据了解，既没有预防措施，也没有治疗措施。 我们的基本假设是，可遗传因素决定了AIN脆弱性的门槛，而生物学因素 而环境变量决定了它的表型。我们建议用药物基因组学方法来处理AIN 果蝇在黑腹果蝇中的策略我们将使用ND2360114菌株，这是Leigh的模型 综合征(一种由NDUFS8突变引起的人类神经退行性疾病)，NDUFS8是 ND23)。ND2360114果蝇暴露于VGA产生了四种显著的表型：(1)幼蝇 对异氟醚和七氟醚(复制人类表型)的行为影响过敏，(2) 中年果蝇在从异氟醚中醒来后24小时内显著死亡，(3)遗传和 环境操纵深刻地调节了死亡率，以及(4)表型正常的ND2360114/苍蝇 从而在高龄时从异氟醚中对AIN敏化。我们将使用ND2360114苍蝇作为 AIN的敏化模型，具有快速、明确的读数。为了研究基因的调节作用 背景关于AIN，我们将使用基因组范围关联研究(GWAS)分析来识别核苷酸 在ND2360114/Fly中修改AIN的多态。来确定杂合突变的范围 增加AIN的风险，我们将在线粒体代谢途径中筛选候选突变。要确定 AIN的关键代谢调节剂，我们将在实验条件下使用RNA-seq，导致不同的 死亡率。 这些研究意义重大，因为接触VGA每年会影响数百万各个年龄段的人，而且 对AIN的担忧是普遍的。暴露在麻醉和手术中的并发症是长期存在的 后果。在评估AIN个体风险时考虑遗传背景是迈向 个性化医疗。了解其病理生理学为知情的预防和治疗提供了一条途径。

Some individuals undergoing anesthesia and surgery will experience anesthetic-induced neurotoxicity (AiN) attributable to volatile general anesthetic agents (VGAs). AiN after exposure to VGAs can present with different phenotypes, including acute neurodegeneration, delirium, lifelong cognitive impairment in children and accelerated or even de novo neurodegeneration in the aged. Despite controversial clinical trials, the FDA, in a far-reaching response to recent data, has issued a warning on the use of VGAs in pregnant women and young children. Furthermore, the American Society of Anesthesiologists' Perioperative Brain Health Initiative has raised awareness of AiN for the aged brain. As neither the pathophysiology of AiN nor its risk factors are understood, there are neither prophylactic nor therapeutic measures. Our underlying hypothesis is that heritable factors determine the threshold for AiN vulnerability while biological and environmental variables shape its phenotype. We propose to approach AiN with a pharmacogenomic strategy in the fruit fly Drosophila melanogaster. We will use the ND2360114 strain, which is a model of Leigh syndrome (a human neurodegenerative disease caused by mutation of NDUFS8, the mammalian ortholog of ND23). Exposure of ND2360114 flies to VGAs results in four striking phenotypes: (1) young flies are equally hypersensitive to the behavioral effects of isoflurane and sevoflurane (reproducing the human phenotype), (2) middle-aged flies incur significant mortality within 24 hours after waking up from isoflurane, (3) genetic and environmental manipulations profoundly modulate mortality, and (4) phenotypically normal ND2360114/+ flies become sensitized to AiN from isoflurane at an advanced age thereby. We will use ND2360114 flies as a sensitized model of AiN with rapid, unambiguous readout. To investigate the modulatory role of genetic background on AiN, we will use genome-wide association study (GWAS) analysis to identify nucleotide polymorphisms that modify AiN in ND2360114/+ flies. To determine the scope of heterozygous mutations that increase the risk of AiN, we will screen candidate mutants in mitochondrial metabolic pathways. To identify key metabolic regulators of AiN, we will use RNA-seq under experimental conditions that result in different mortality rates. These studies are significant because exposure to VGA affects millions of people of all ages every year and concerns of AiN are widespread. Complications from exposure to anesthesia and surgery have long-lasting consequences. Considering genetic background when assessing the individual risk of AiN is a step towards personalized medicine. Understanding its pathophysiology offers a path to informed prevention and treatment.