title: Subclinical carbon monoxide limits apoptosis in the developing brain after isoflurane exposure.
abstract: 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.
authors.affiliation: 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.
authors.forename: Ying
authors.initials: Y
authors.lastname: Cheng
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Levy
mesh_terms: D018685:Anesthetics, Inhalation / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000187:drug effects*; D001921:Brain / Q000187:drug effects*; D002248:Carbon Monoxide / Q000494:pharmacology*; D002263:Carboxyhemoglobin / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism; D003578:Cytochrome-c Peroxidase / Q000037:antagonists & inhibitors / Q000378:metabolism; D045304:Cytochromes c / Q000378:metabolism; D005260:Female; D006418:Heme / Q000378:metabolism; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D007530:Isoflurane / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D051379:Mice; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D011247:Pregnancy
chemical_list: D018685:Anesthetics, Inhalation; D006418:Heme; D002248:Carbon Monoxide; D045304:Cytochromes c; D002263:Carboxyhemoglobin; D007530:Isoflurane; D003578:Cytochrome-c Peroxidase; D053148:Caspase 3