Carbon monoxide exposure and anesthesia-induced neurotoxicity

常用的麻醉药会在发育中的哺乳动物大脑中引起广泛的神经变性。 神经毒性是由于半胱氨酸天冬氨酸氨基转移酶通过线粒体途径被激活而发生的，随后 死亡受体激活和神经营养因子激活通路。一氧化碳(CO)具有抗衰老作用 在低流量麻醉(LFA)中，细胞凋亡特性和呼出的内源性一氧化碳经常被重新呼吸 导致亚临床一氧化碳暴露的婴儿和儿童。我们的知识有一个很大的差距，因为 目前尚不清楚一氧化碳暴露是否会抑制麻醉诱导的神经细胞凋亡。背后的具体假设 这一建议是低浓度的吸入CO可防止麻醉诱导的神经毒性。这个 本提案中概述的实验旨在确定CO介导的抑制作用的机制 异氟醚诱导神经细胞凋亡，以确定同时一氧化碳和异氟醚的神经学后果 新生小鼠暴露异氟醚，并建立LFA期间CO再呼吸的大型动物模型。 这项建议将为在LFA期间开发CO再呼吸作为预防措施奠定基础 旨在防止麻醉引起的神经变性的干预措施。

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 to determine the mechanism of CO-mediated inhibition of isoflurane-induced neuroapoptosis, to identify the neurologic consequences of simultaneous CO and isoflurane exposure in newborn mice, and to develop a large animal model of CO re-breathing during LFA. 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.