Heightened stress response and cognitive impairment after repeated neonatal sevoflurane exposures might be linked to excessive GABAAR-mediated depolarization

• Published in: Journal of anesthesia 2016-10, Vol.30 (5), p.834-841
• Main Authors: Liu, Guanghai, Zhu, Tiangui, Zhang, Aihua, Li, Feng, Qian, Weidong, Qian, Bin
• Format: Article
• Language: English
• Subjects: Anesthesiology; Anesthetics, Inhalation - toxicity; Animals; Animals, Newborn; Bumetanide - pharmacology; Cognitive Dysfunction - chemically induced; Cognitive Dysfunction - psychology; Corticosterone - blood; Critical Care Medicine; Diuretics - pharmacology; Emergency Medicine; Female; Intensive; Male; Maze Learning - drug effects; Medicine; Medicine & Public Health; Memory Disorders - chemically induced; Memory Disorders - psychology; Methyl Ethers - toxicity; Original Article; Pain Medicine; Pregnancy; Rats; Rats, Sprague-Dawley; Receptors, GABA-A - drug effects; Sodium-Potassium-Chloride Symporters - drug effects; Stress, Psychological - chemically induced; Stress, Psychological - psychology
• ISSN: 0913-8668; 1438-8359
• DOI: 10.1007/s00540-016-2215-0

Objective Children with repeated exposures to anesthesia at an early age are at an increased risk of cognitive impairment. Data in the literature link increased developmental depolarizing γ-aminobutyric acid (GABA) type A receptor (GABA A R) at younger age to neurodevelopmental disorders. Here we investigated the involvement of GABAergic signaling during development in mediating the adverse effects of repeated sevoflurane exposures. Methods Sprague–Dawley male rats received repeated exposures to 3 % sevoflurane for 2 h daily for 3 consecutive days on postnatal days (P) 4, 5, and 6; maternally separated and unseparated rats served as controls. A subgroup of rats received three injections of the Na + –K + –2Cl − cotransporter inhibitor, bumetanide (1.82 mg/kg, intraperitoneally) 15 min prior to initiation of each sevoflurane exposure. Results The results showed that repeated neonatal sevoflurane exposures contribute to learning and memory impairment in the Morris water maze (MWM) at P60. The corticosterone level was significantly increased immediately after repeated neonatal sevoflurane exposures. Repeated neonatal sevoflurane exposures heightened the secretion of corticosterone in response to stress in P7 and P60 rats. Pretreatment of male rats prior to each sevoflurane exposure with bumetanide attenuated the corticosterone level immediately after repeated neonatal sevoflurane exposures, normalized endocrine response to stress at P7 and P60, and attenuated the sevoflurane-induced learning and memory impairment in the MWM. Conclusion These data suggested that the heightened stress response and cognitive impairment after repeated neonatal sevoflurane exposures might be linked to excessive GABA A R-mediated depolarization.