title: Isoflurane-induced neuroapoptosis in the developing brain of nonhypoglycemic mice.
abstract: Drugs that suppress neuronal activity, including general anesthetics used in pediatric and obstetric medicine, trigger neuroapoptosis in the developing rodent brain. Exposure of infant rats for 6 hours to a combination of anesthetic drugs (midazolam, nitrous oxide, isoflurane) reportedly causes widespread apoptotic neurodegeneration, followed by lifelong cognitive deficits. Isoflurane, the dominant ingredient in this triple cocktail, has not been evaluated individually for apoptogenic potential. It was recently reported that (1) the minimum alveolar concentration (MAC) for anesthetizing infant mice with isoflurane is 2.26%, and; (2) that infant mice, without assisted respiration, maintain normal arterial oxygen values but become hypoglycemic when exposed to isoflurane 3% for 30 minutes, then 1.8% for 1 hour (1.46 MAC-hours). In the present experiments, infant mice were exposed to isoflurane at various sub-MAC concentrations and durations, and the brains were evaluated quantitatively 5 hours after initiation of anesthesia exposure to determine the number of neuronal profiles undergoing apoptosis. Blood glucose values were also determined under each of these conditions. All conditions tested (isoflurane at 0.75% for 4 h, 1.5% for 2 h, 2.0% for 1 h) triggered a statistically significant increase in neuroapoptosis compared with the rate of spontaneous apoptosis in littermate controls. Blood glucose determinations ruled out hypoglycemia as a potential cause of the brain damage. It is concluded that exposure to sub-MAC concentrations of isoflurane for one or more hours triggers neuroapoptosis in the infant mouse brain. These findings are consistent with other recent evidence demonstrating that brief exposure to ethanol, ketamine, or midazolam triggers neuroapoptosis in the developing mouse brain.
authors.affiliation: Department of Psychiatry, Washington University School of Medicine, St Louis, MO 63110, USA.
authors.forename: Stephen A
authors.initials: SA
authors.lastname: Johnson
authors.forename: Chainllie
authors.initials: C
authors.lastname: Young
authors.forename: John W
authors.initials: JW
authors.lastname: Olney
mesh_terms: D018685:Anesthetics, Inhalation / Q000633:toxicity*; D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000187:drug effects*; D001786:Blood Glucose / Q000378:metabolism; D001921:Brain / Q000254:growth & development / Q000473:pathology*; D002452:Cell Count; D007003:Hypoglycemia / Q000473:pathology; D007530:Isoflurane / Q000633:toxicity*; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000187:drug effects / Q000473:pathology*; D011650:Pulmonary Alveoli / Q000187:drug effects / Q000378:metabolism
chemical_list: D018685:Anesthetics, Inhalation; D001786:Blood Glucose; D007530:Isoflurane