PERIOPERATIVE MEDICINE Isoflurane Causes Greater Neurodegeneration Than an Equivalent Exposure of Sevoflurane in the Developing Brain of Neonatal Mice

ABSTRACT Background: We hypothesized that isoflurane has a greater potency to induce neurodegeneration than sevoflurane in the developing brains of neonatal mice based on our previous studies in cell culture. Methods: We treated 7-day-old mice with either 0.75% isoflurane or 1.1% sevoflurane (ϳ0.5 minimum alveolar concentration) for 6 h and then obtained blood and brain samples at 2 h after the anesthesia treatment for determination of neuroapoptosis in different brain regions and the neurodegenerative biomarker S100␤ in the blood. The mechanisms of neurodegeneration induced by isoflurane or sevoflurane were also compared by determining protein expressions of the cell cycle and apoptosis-related proteins. In separate groups, memory and learning ability were evaluated through the use of Morris Water Maze testing in mice at postnatal day 42 after anesthesia treatment at postnatal day 7. Results: Isoflurane but not sevoflurane significantly increased the neurodegenerative biomarker S100␤ in the blood. Isoflurane treatments significantly increased apoptosis indicated by the activation of caspase-3 and elevation of poly-(ADP-ribose) polymerase in different brain regions. An equipotent exposure of sevoflurane tended to increase apoptosis in hippocampal and cortex areas but was significantly less potent than isoflurane. Neither isoflurane nor sevoflurane significantly changed protein levels of glyceraldehyde-3-phosphate dehydrogenase, ␤-site amyloid ␤-precursor protein-cleaving enzyme, and cell cycle regulatory proteins (CDK4, cyclin D1). Isoflurane and sevoflurane at the selected exposures did not significantly alter memory and learning ability. Conclusion: At equipotent exposures, isoflurane has a greater potency than sevoflurane to cause neurodegeneration in the developing brains of neonatal mice. N UMEROUS studies during the past few years have demonstrated the potential deleterious effects of anesthetic exposure to neonatal animals with regard to neurohistopathologic changes and long-term abnormal social behavior and cognitive dysfunction. Studies on a variety of animals ranging from rodents to rhesus monkeys have shown increased neuroapoptosis in the postnatal developing brains of these newborn animals when exposed to both intravenous and inhaled anesthetic agents. 1-4 Our recent study also demonstrated isoflurane-induced neurodegeneration represented by the elevation of a neurodegenerative biomarker in blood, S100␤, and apoptosis in various brain regions in the prenatal developing rat brain. 5 Rodent studies have also demonstrated persistent learning deficits and social behavio