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.
The public health relevance of this proposal relates to development of low-flow anesthesia and carbon monoxide re-breathing as an approach to protect the developing brain from toxicity during anesthesia exposure. PUBLIC HEALTH RELEVANCE: Anesthesia-induced neuroapoptosis results in behavioral impairments and cognitive deficits during mammalian development. Carbon monoxide (CO) has anti-apoptotic properties and exhaled endogenous CO is commonly re-breathed during low-flow anesthesia (LFA) resulting in exposure. The experiments outlined in this proposal will lay the groundwork needed to establish CO re-breathing during LFA as a standard paradigm to prevent anesthesia-induced neurodegeneration. The public health relevance of this proposal relates to development of this specific therapeutic intervention as an approach to protect the developing brain from toxicity during anesthesia exposure.
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