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.

Isoflurane Anesthesia Induced Persistent, Progressive Memory Impairment, Caused a Loss of Neural Stem Cells, and Reduced Neurogenesis in Young, but Not Adult, Rodents

“…Loepke et al (2006) found that when infant mice were exposed to isoflurane (3% for 30 mins followed by 1.8% for 1 h) without assisted ventilation, the MAP remained stable and blood gas values did not vary markedly from unanesthetized controls. Johnson et al (2008) found that 2% isoflurane for 1 h had no effect on blood glucose in immature mice and the minimum alveolar concentration of isoflurane is 1.6% for human neonates (LeDez and Lerman 1987). In this study, we found that neither single nor repeated (up to 4) isoflurane exposures for 35 mins, without assisted ventilation, had any apparent effect on the MAP.…”

Diabetes increases brain damage caused by severe hypoglycemia

“…However, in the laboratory setting, hyperinsulinemic hypoglycemic clamp methods were employed to control the absolute nadir and duration of hypoglycemia to reproducibly induce neuronal damage. A major confounding factor in laboratory severe hypoglycemia experiments is the use of anesthetic agents, which differs from real-world hypoglycemia because anesthesia 1) markedly reduces brain glucose uptake, which may increase brain damage, 2) abrogates seizure activity often associated with severe hypoglycemia, 3) induces hypothermia, 4) impairs the increased blood pressure (Cushing) response to hypoglycemia, and 5) has been shown to be neurotoxic (1,10,21,22,32). To circumvent these technical problems and consistently recreate real-world hypoglycemic conditions, our experiments were conducted in awake, freely mobile rodents without the confounding effects of anesthesia.…”

Isoflurane but not Fentanyl Causes Apoptosis in Immature Primary Neuronal Cells

“…In newborn mice, general anaesthesia with 1.5 Vol.% isoflurane has been found to cause a 4-11 fold increase of neuronal death in various brain regions, as compared to controls. [10,28,29] A 6-hour isoflurane exposure eliminates approximately 2% of cortical neurons [14]. Apoptosis appears to be the predominant mode of isoflurane-induced death, as evidenced by caspase-3 cleavage [10].…”

“…[10,28,29] A 6-hour isoflurane exposure eliminates approximately 2% of cortical neurons [14]. Apoptosis appears to be the predominant mode of isoflurane-induced death, as evidenced by caspase-3 cleavage [10]. Notably, mice genetically deficient in the apoptosis-triggering cell surface receptors Fas (CD95) or FasL (CD95L) show reduced isofluraneinduced neuronal cell death [30].…”

“…Exposure to isoflurane, which affects various cell types outside and inside the brain [8,24], causes a panoply of cardiorespiratory and metabolic side effects [10]. Its use in newborn rodents is associated with considerable mortality [25].…”