title: The effects of neonatal isoflurane exposure in mice on brain cell viability, adult behavior, learning, and memory.
abstract: BACKGROUND
  Volatile anesthetics, such as isoflurane, are widely used in infants and neonates. Neurodegeneration and neurocognitive impairment after exposure to isoflurane, midazolam, and nitrous oxide in neonatal rats have raised concerns regarding the safety of pediatric anesthesia. In neonatal mice, prolonged isoflurane exposure triggers hypoglycemia, which could be responsible for the neurocognitive impairment. We examined the effects of neonatal isoflurane exposure and blood glucose on brain cell viability, spontaneous locomotor activity, as well as spatial learning and memory in mice.
  
  
  METHODS
  Seven-day-old mice were randomly assigned to 6 h of 1.5% isoflurane with or without injections of dextrose or normal saline, or to 6 h of room air without injections (no anesthesia). Arterial blood gases and glucose were measured. After 2 h, 18 h, or 11 wk postexposure, cellular viability was assessed in brain sections stained with Fluoro-Jade B, caspase 3, or NeuN. Nine weeks postexposure, spontaneous locomotor activity was assessed, and spatial learning and memory were evaluated in the Morris water maze using hidden and reduced platform trials.
  
  
  RESULTS
  Apoptotic cellular degeneration increased in several brain regions early after isoflurane exposure, compared with no anesthesia. Despite neonatal cell loss, however, adult neuronal density was unaltered in two brain regions significantly affected by the neonatal degeneration. In adulthood, spontaneous locomotor activity and spatial learning and memory performance were similar in all groups, regardless of neonatal isoflurane exposure. Neonatal isoflurane exposure led to an 18% mortality, and transiently increased Paco(2), lactate, and base deficit, and decreased blood glucose levels. However, hypoglycemia did not seem responsible for the neurodegeneration, as dextrose supplementation failed to prevent neuronal loss.
  
  
  CONCLUSIONS
  Prolonged isoflurane exposure in neonatal mice led to increased immediate brain cell degeneration, however, no significant reductions in adult neuronal density or deficits in spontaneous locomotion, spatial learning, or memory function were observed.
authors.affiliation: Department of Anesthesia, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229, USA. andreas.loepke@cchmc.or
authors.forename: Andreas W
authors.initials: AW
authors.lastname: Loepke
authors.forename: George K
authors.initials: GK
authors.lastname: Istaphanous
authors.forename: John J
authors.initials: JJ
authors.lastname: McAuliffe
authors.forename: Lili
authors.initials: L
authors.lastname: Miles
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Hughes
authors.forename: John C
authors.initials: JC
authors.lastname: McCann
authors.forename: Kathryn E
authors.initials: KE
authors.lastname: Harlow
authors.forename: C Dean
authors.initials: CD
authors.lastname: Kurth
authors.forename: Michael T
authors.initials: MT
authors.lastname: Williams
authors.forename: Charles V
authors.initials: CV
authors.lastname: Vorhees
authors.forename: Steve C
authors.initials: SC
authors.lastname: Danzer
mesh_terms: D018685:Anesthetics, Inhalation / Q000633:toxicity*; D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000187:drug effects*; D001522:Behavior, Animal / Q000187:drug effects*; D001786:Blood Glucose / Q000187:drug effects; D001921:Brain / Q000187:drug effects* / Q000473:pathology / Q000503:physiopathology; D002245:Carbon Dioxide / Q000097:blood; D002470:Cell Survival / Q000187:drug effects; D005260:Female; D005947:Glucose / Q000008:administration & dosage; D006863:Hydrogen-Ion Concentration; D007530:Isoflurane / Q000633:toxicity*; D019344:Lactic Acid / Q000097:blood; D008297:Male; D018782:Maze Learning / Q000187:drug effects*; D008568:Memory / Q000187:drug effects*; D051379:Mice; D008810:Mice, Inbred C57BL; D009043:Motor Activity / Q000187:drug effects; D009410:Nerve Degeneration / Q000139:chemically induced* / Q000473:pathology / Q000503:physiopathology; D009474:Neurons / Q000187:drug effects / Q000473:pathology; D010100:Oxygen / Q000097:blood; D013997:Time Factors
chemical_list: D018685:Anesthetics, Inhalation; D001786:Blood Glucose; D002245:Carbon Dioxide; D019344:Lactic Acid; D007530:Isoflurane; D005947:Glucose; D010100:Oxygen