Enhanced Histone Lysine Methyltransferase G9a Might Contribute to Repeated Sevoflurane Exposure-Induced Apoptosis and Cognitive Impairment in the Developing Brain

Abstract

Background: Early exposure to sevoflurane induces neurodegeneration in the developing brain and subsequent long-term neurobehavioral abnormalities in animals and humans. However, the underlying molecular mechanisms remain unclear. We explored whether hippocampal histone lysine methyltransferase G9a plays a role in sevoflurane-induced cognitive impairment in neonatal rats.Methods: The anesthesia was induced with 6% sevoflurane for 3 minutes and maintained with 3% sevoflurane for 1 hour and 57 minutes. The anesthesia was applied for three successive days from postnatal day 5 (P5) to P7. The inhibitor of G9a (Bix-01294, Bix) or vehicle was given 15 minutes before the sevoflurane exposure, respectively. The rats were allocated into four groups: control + vehicle (Con + Veh) group, control + Bix (Con + Bix) group, sevoflurane + vehicle (Sev + Veh) group, and sevoflurane + Bix (Sev + Bix) group. Cognitive performance was evaluated by the open field, fear conditioning, and Morris water maze tests at P35, P39–41, and P49–55, respectively. After the last sevoflurane exposure or before the open field test, the brain tissues were harvested for further analysis.Results: The freezing time to context in the fear conditioning test and the time spent in the target quadrant in the Morris water maze test were significantly decreased in the Sev + Veh group compared with the Con + Veh group. Sevoflurane exposure increased cleaved caspase-3, enhanced G9a activity, and subsequently upregulated dimethylation lysine 9 of histone H3 (H3K9me2) in the hippocampus. By contrast, Bix treatment could rescue these changes.Conclusion: Our results demonstrate that the G9a-mediated enhancement of H3K9me2 expression might be involved in the sevoflurane-induced neuroapoptosis and cognitive impairment in the developing brain. Citation: Jiao-Jiao Yang, Min-Ze Xie, Ling-Sha Ju, Min Jia, Jian-Jun Yang. et al. Enhanced histone lysine methyltransferase G9a might contribute to repeated sevoflurane exposure-induced apoptosis and cognitive impairment in the developing brain. J Anesth Perioper Med 2016; 3: 1-10. doi: 10.24015/JAPM.2016.0001This is an open-access article, published by Evidence Based Communications (EBC). This work is licensed under the Creative Commons Attribution 4.0 International License, which permits unrestricted use, distribution, and reproduction in any medium or format for any lawful purpose. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.