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Subclinical Carbon Monoxide Limits Apoptosis in the Developing Brain After Isoflurane Exposure

Cheng, Ying; Levy, Richard J. MD

doi: 10.1213/ANE.0000000000000030
Pediatric Neuroscience: Research Report

BACKGROUND: Volatile anesthetics cause widespread apoptosis in the developing brain. Carbon monoxide (CO) has antiapoptotic properties, and exhaled endogenous CO is commonly rebreathed during low-flow anesthesia in infants and children, resulting in subclinical CO exposure. Thus, we aimed to determine whether CO could limit isoflurane-induced apoptosis in the developing brain.

METHODS: Seven-day-old male CD-1 mouse pups underwent 1-hour exposure to 0 (air), 5, or 100 ppm CO in air with or without isoflurane (2%). We assessed carboxyhemoglobin levels, cytochrome c peroxidase activity, and cytochrome c release from forebrain mitochondria after exposure and quantified the number of activated caspase-3 positive cells and TUNEL positive nuclei in neocortex, hippocampus, and hypothalamus/thalamus.

RESULTS: Carboxyhemoglobin levels approximated those expected in humans after a similar time-weighted CO exposure. Isoflurane significantly increased cytochrome c peroxidase activity, cytochrome c release, the number of activated caspase-3 cells, and TUNEL positive nuclei in the forebrain of air-exposed mice. CO, however, abrogated isoflurane-induced cytochrome c peroxidase activation and cytochrome c release from forebrain mitochondria and decreased the number of activated caspase-3 positive cells and TUNEL positive nuclei after simultaneous exposure with isoflurane.

CONCLUSIONS: Taken together, the data indicate that CO can limit apoptosis after isoflurane exposure via inhibition of cytochrome c peroxidase depending on concentration. Although it is unknown whether CO directly inhibited isoflurane-induced apoptosis, it is possible that low-flow anesthesia designed to target rebreathing of specific concentrations of CO may be a desired strategy to develop in the future in an effort to prevent anesthesia-induced neurotoxicity in infants and children.

From the Division of Anesthesiology and Pain Medicine, Children’s National Medical Center, The George Washington University School of Medicine and Health Sciences, Washington, DC.

Accepted for publication October 4, 2013.

Funding: None.

The authors declare no conflicts of interest.

Reprints will not be available from the authors.

Address correspondence to Richard J. Levy, MD, Division of Anesthesiology and Pain Medicine, Children’s National Medical Center, 111 Michigan Ave., NW, Washington, DC 20010. Address e-mail to rlevy@cnmc.org.

© 2014 International Anesthesia Research Society