Carbon monoxide exposure and anesthesia-induced neurotoxicity

一氧化碳暴露和麻醉引起的神经毒性

• 批准号: 8735967
• 负责人: Richard J Levy
• 金额: $ 1.98万
• 依托单位: CHILDREN'S RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-18 至 2014-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8735967
• 关键词: Anesthesia procedures; Anesthetics; Apoptosis; Apoptotic; Body Weight; Brain; Breathing; Carbon Monoxide; Caspase; Cell Nucleus; Cell Survival; Cells; Cessation of life; Child; Clinical; Cognitive deficits; Cytochrome c Peroxidase; Development; Dose; Dropout; Electron Transport; Electrons; Exhalation; Exposure to; Homeostasis; Hour; Immunoblot Analysis; Impairment; In Situ Nick-End Labeling; Infant; Isoflurane; Knowledge; Learning; Measures; Mediating; Mediator of activation protein; Memory; Mitochondria; Mus; Neocortex; Nerve Degeneration; Nerve Growth Factor Receptors; Neurocognitive; Neurologic; Neurons; Newborn Infant; Oxidative Stress; Pathway interactions; Phosphorylation; Phosphotransferases; Property; Proteins; Signal Transduction; Social Behavior; Socialization; Staining method; Stains; Testing; Therapeutic Intervention; Toxic effect; Work; behavioral impairment; brain size; caspase-3; caspase-8; caspase-9; cresyl violet; cytochrome c; cytochrome c oxidase; mitochondrial dysfunction; neuron apoptosis; neuron loss; neurotoxicity; prevent; public health relevance; pup; receptor; research study; therapy design

DESCRIPTION (provided by applicant): Commonly used anesthetics cause widespread neurodegeneration in the developing mammalian brain. Neurotoxicity occurs due to caspase activation via the mitochondrial pathway of apoptosis followed by activation of death receptor and neurotrophic-factor activated pathways. Carbon monoxide (CO) has anti-apoptotic properties and exhaled endogenous CO is commonly re-breathed during low-flow anesthesia (LFA) in infants and children resulting in sub-clinical CO exposure. There is a major gap in our knowledge because it is unknown if CO exposure inhibits anesthesia-induced neuroapoptosis. The specific hypothesis behind this proposal is that low concentrations of inspired CO prevent anesthesia-induced neurotoxicity. The experiments outlined in this proposal are aimed at determining the mechanism of CO-mediated inhibition of isoflurane-induced neuroapoptosis, identifying the neurologic consequences of simultaneous CO and isoflurane exposure in newborn mice, and assessing the effect of CO and isoflurane on regulators of mitochondrial homeostasis and mediators of oxidative stress. This proposal will lay the groundwork for development of CO re-breathing during LFA as a preventative intervention designed to protect against anesthesia-induced neurodegeneration.

描述（由申请人提供）：常用的麻醉剂会导致哺乳动物大脑发育中广泛的神经变性。神经毒性的发生是由于通过线粒体凋亡途径激活半胱天冬酶，随后激活死亡受体和神经营养因子激活途径。一氧化碳 (CO) 具有抗细胞凋亡特性，婴儿和儿童在低流量麻醉 (LFA) 期间通常会重新吸入呼出的内源性 CO，从而导致亚临床 CO 暴露。我们的知识存在重大差距，因为尚不清楚 CO 暴露是否会抑制麻醉诱导的神经细胞凋亡。该提议背后的具体假设是低浓度的吸入二氧化碳可以防止麻醉引起的神经毒性。本提案中概述的实验旨在确定 CO 介导的异氟醚诱导的神经细胞凋亡抑制机制，确定新生小鼠同时接触 CO 和异氟醚的神经系统后果，并评估 CO 和异氟醚对线粒体稳态调节剂的影响和氧化应激介质。该提案将为 LFA 期间二氧化碳再呼吸的发展奠定基础，作为一种预防性干预措施，旨在防止麻醉引起的神经退行性变。