Carbon monoxide exposure and anesthesia-induced neurotoxicity

描述（由申请人提供）：常用麻醉剂导致发育中哺乳动物大脑的广泛神经变性。神经毒性的发生是由于半胱天冬酶通过细胞凋亡的线粒体途径活化，随后是死亡受体和神经营养因子活化途径的活化。一氧化碳（CO）具有抗凋亡特性，在婴儿和儿童的低流量麻醉（LFA）期间，呼出的内源性CO通常会被重新吸入，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。这一提议背后的具体假设是，低浓度的吸入CO防止麻醉诱导的神经毒性。本提案中概述的实验旨在确定CO介导的异氟烷诱导的神经细胞凋亡抑制机制，确定新生小鼠同时暴露于CO和异氟烷的神经学后果，并评估CO和异氟烷对线粒体稳态调节剂和氧化应激介质的影响。该建议将为LFA期间CO再呼吸的发展奠定基础，作为旨在防止麻醉诱导的神经变性的预防性干预措施。

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.