title: Carbon monoxide incompletely prevents isoflurane-induced defects in murine neurodevelopment.
abstract: Commonly used anesthetics have been shown to disrupt neurodevelopment in preclinical models. It has been proposed that such anesthesia-induced neurotoxicity is mediated by apoptotic neurodegeneration in the immature brain. Low dose carbon monoxide (CO) exerts cytoprotective properties and we have previously demonstrated that CO inhibits isoflurane-induced apoptosis in the developing murine brain. Here we utilized anti-apoptotic concentrations of CO to delineate the role of apoptotic neurodegeneration in anesthesia-induced neurotoxicity by assessing the effect of CO on isoflurane-induced defects in neurodevelopment.
  
  
  
  C57Bl/6 mouse pups underwent 1-hour exposure to 0ppm (air), 5ppm, or 100ppm CO in air with or without isoflurane on postnatal day 7. Cohorts were evaluated 5-7weeks post exposure with T-maze cognitive testing followed by social behavior assessment. Brain size, whole brain cellular content, and neuronal density in primary somatosensory cortex and hippocampal CA3 region were measured as secondary outcomes 1-week or 5-7weeks post exposure along with 7-day old, unexposed controls.
  
  
  
  Isoflurane impaired memory acquisition and resulted in abnormal social behavior. Low concentration CO abrogated anesthetic-induced defects in memory acquisition, however, it also resulted in impaired spatial reference memory and social behavior abnormalities. Changes in brain size, cellular content, and neuronal density over time related to the age of the animal and were unaffected by either isoflurane or CO.
  
  
  
  Anti-apoptotic concentrations of CO incompletely prevented isoflurane-induced defects in neurodevelopment, lacked concentration-dependent effects, and only provided protection in certain domains suggesting that anesthesia-related neurotoxicity is not solely mediated by activation of the mitochondrial apoptosis pathway.
authors.affiliation: The Sheikh Zayed Institute for Pediatric Surgical Innovation, Division of Pain Medicine, Children's National Health System, Children's Research Institute, The George Washington University School of Medicine and Health Sciences, United States.
authors.forename: Li
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Anesthesiology, Columbia University Medical Center, United States.
authors.forename: Aili
authors.initials: A
authors.lastname: Wang
authors.affiliation: Rutgers New Jersey Medical School, United States.
authors.forename: William W
authors.initials: WW
authors.lastname: Supplee
authors.affiliation: Department of Anesthesiology, Columbia University Medical Center, United States.
authors.forename: Kayla
authors.initials: K
authors.lastname: Koffler
authors.affiliation: Center for Genetic Medicine Research, Children's National Health System, Children's Research Institute, The George Washington University School of Medicine and Health Sciences, United States.
authors.forename: Ying
authors.initials: Y
authors.lastname: Cheng
authors.affiliation: The Sheikh Zayed Institute for Pediatric Surgical Innovation, Division of Pain Medicine, Children's National Health System, Children's Research Institute, The George Washington University School of Medicine and Health Sciences, United States.
authors.forename: Zenaide M N
authors.initials: ZMN
authors.lastname: Quezado
authors.affiliation: Department of Anesthesiology, Columbia University Medical Center, United States. Electronic address: rl2740@cumc.columbia.edu.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Levy
mesh_terms: D018685:Anesthetics, Inhalation / Q000633:toxicity; D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000254:growth & development* / Q000473:pathology; D056654:CA3 Region, Hippocampal / Q000473:pathology; D002248:Carbon Monoxide / Q000494:pharmacology*; D005260:Female; D007530:Isoflurane / Q000037:antagonists & inhibitors / Q000633:toxicity*; D008297:Male; D008569:Memory Disorders / Q000139:chemically induced / Q000517:prevention & control; D051379:Mice; D009410:Nerve Degeneration / Q000139:chemically induced / Q000517:prevention & control*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D012920:Social Behavior Disorders / Q000139:chemically induced / Q000517:prevention & control; D013003:Somatosensory Cortex / Q000473:pathology
chemical_list: D018685:Anesthetics, Inhalation; D018696:Neuroprotective Agents; D002248:Carbon Monoxide; D007530:Isoflurane
keywords: Anesthesia; Apoptosis; Brain; Carbon monoxide; Development; Isoflurane; Neurotoxicity; Social behavior; Spatial reference memory