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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM103842-02
Application #
8735967
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Program Officer
Cole, Alison E
Project Start
2013-09-18
Project End
2018-06-30
Budget Start
2014-07-01
Budget End
2015-06-30
Support Year
2
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Children's Research Institute
Department
Type
DUNS #
City
Washington
State
DC
Country
United States
Zip Code
20010
Levy, Richard J (2016) Carbon monoxide and anesthesia-induced neurotoxicity. Neurotoxicol Teratol :
Levy, Richard J (2016) Anesthesia-Related Carbon Monoxide Exposure: Toxicity and Potential Therapy. Anesth Analg 123:670-81
Levy, Richard J; Herbstman, Julie B; Bosnjak, Zeljko J et al. (2016) Biomarkers, Genetics, and Epigenetic Studies to Explore the Neurocognitive Effects of Anesthesia in Children. J Neurosurg Anesthesiol :
Onwugbufor, Michael; Levy, Richard J; Zurakowski, David et al. (2016) Myocardial cytochrome oxidase activity increases with age and hypoxemia in patients with congenital heart disease. Perfusion :
Cheng, Ying; Mitchell-Flack, Marisa J; Wang, Aili et al. (2015) Carbon monoxide modulates cytochrome oxidase activity and oxidative stress in the developing murine brain during isoflurane exposure. Free Radic Biol Med 86:191-9
Levy, Richard J (2015) Carbon monoxide pollution and neurodevelopment: A public health concern. Neurotoxicol Teratol 49:31-40
Cheng, Ying; He, Linda; Prasad, Vidhya et al. (2015) Anesthesia-Induced Neuronal Apoptosis in the Developing Retina: A Window of Opportunity. Anesth Analg 121:1325-35
Cheng, Ying; Levy, Richard J (2014) Subclinical carbon monoxide limits apoptosis in the developing brain after isoflurane exposure. Anesth Analg 118:1284-92
Jain, Parag; Spaeder, Michael C; Donofrio, Mary T et al. (2014) Detection of alpha II-spectrin breakdown products in the serum of neonates with congenital heart disease*. Pediatr Crit Care Med 15:229-35
Cheng, Ying; Corbin, Joshua G; Levy, Richard J (2013) Programmed cell death is impaired in the developing brain of FMR1 mutants. Dev Neurosci 35:347-58