title: Hypermethylation of Hippocampal Synaptic Plasticity-Related genes is Involved in Neonatal Sevoflurane Exposure-Induced Cognitive Impairments in Rats.
abstract: General anesthetics given to immature rodents cause delayed neurobehavioral abnormalities via incompletely understood mechanisms. DNA methylation, one of the epigenetic modifications, is essential for the modulation of hippocampal synaptic plasticity through regulating the related genes. Therefore, we investigated whether abnormalities in the hippocampal DNA methylation of synaptic plasticity-related genes are involved in neonatal sevoflurane exposure-induced cognitive impairments in rats. Male Sprague-Dawley rats were exposed to 3 % sevoflurane or 30 % oxygen/air for 2 h daily from postnatal day 7 (P7) to P9 and were treated with DNA methyltransferases (DNMTs) inhibitor 5-aza-2-deoxycytidine (5-AZA) or vehicle 1 h before the first sevoflurane exposure on P7. The rats were euthanized 1, 6, 24 h, and 30 days after the last sevoflurane exposure, and the brain tissues were harvested for biochemical analysis. Cognitive functions were evaluated by the open field, fear conditioning, and Morris water maze (MWM) tests on P39, P41-43, and P50-57, respectively. In the present study, repeated neonatal sevoflurane exposure resulted in hippocampus-dependent cognitive impairments as assessed by fear conditioning and MWM tests. The cognitive impairments were associated with the increased DNMTs and hypermethylation of brain-derived neurotrophic factor (BDNF) and Reelin genes, and subsequent down-regulation of BDNF and Reelin genes, which finally led to the decrease of dendritic spines in the hippocampal pyramidal neurons in adolescent rats. Notably, pretreatment with 5-AZA reversed these sevoflurane-induced abnormalities. In conclusion, our results suggest that hypermethylation of hippocampal BDNF and Reelin is involved in neonatal sevoflurane exposure-induced cognitive impairments.
authors.affiliation: Department of Anesthesiology, Jinling Hospital, School of Medicine, Nanjing University, Nanjing, China.
authors.forename: Ling-sha
authors.initials: LS
authors.lastname: Ju
authors.affiliation: Department of Anesthesiology, Jinling Hospital, School of Medicine, Nanjing University, Nanjing, China.
authors.forename: Min
authors.initials: M
authors.lastname: Jia
authors.affiliation: Department of Anesthesiology, First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Sun
authors.affiliation: Department of Anesthesiology, Jinling Hospital, School of Medicine, Nanjing University, Nanjing, China.
authors.forename: Xiao-ru
authors.initials: XR
authors.lastname: Sun
authors.affiliation: Department of Anesthesiology, Jinling Hospital, School of Medicine, Nanjing University, Nanjing, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Department of Anesthesiology, Jinling Hospital, School of Medicine, Nanjing University, Nanjing, China.
authors.forename: Mu-huo
authors.initials: MH
authors.lastname: Ji
authors.affiliation: Department of Anesthesiology, Jinling Hospital, School of Medicine, Nanjing University, Nanjing, China.
authors.forename: Jian-jun
authors.initials: JJ
authors.lastname: Yang
authors.affiliation: Department of Anesthesiology, First Affiliated Hospital of Nanjing Medical University, Nanjing, China. zywang1970@126.com.
authors.forename: Zhong-yun
authors.initials: ZY
authors.lastname: Wang
mesh_terms: D018685:Anesthetics, Inhalation / Q000008:administration & dosage*; D000818:Animals; D000831:Animals, Newborn; D001374:Azacitidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics; D015816:Cell Adhesion Molecules, Neuronal / Q000235:genetics; D003072:Cognition Disorders / Q000139:chemically induced / Q000201:enzymology* / Q000235:genetics*; D003213:Conditioning, Psychological / Q000187:drug effects / Q000502:physiology; D019175:DNA Methylation; D015254:DNA Modification Methylases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000077209:Decitabine; D049229:Dendritic Spines / Q000187:drug effects / Q000473:pathology; D016326:Extracellular Matrix Proteins / Q000235:genetics; D005239:Fear / Q000187:drug effects / Q000523:psychology; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism* / Q000473:pathology; D008297:Male; D018782:Maze Learning / Q000187:drug effects / Q000502:physiology; D008738:Methyl Ethers / Q000008:administration & dosage*; D051783:Methyl-CpG-Binding Protein 2 / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000235:genetics; D009473:Neuronal Plasticity / Q000187:drug effects*; D017966:Pyramidal Cells / Q000187:drug effects / Q000473:pathology; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D000091042:Reelin Protein; D012697:Serine Endopeptidases / Q000235:genetics; D000077149:Sevoflurane
chemical_list: D018685:Anesthetics, Inhalation; D019208:Brain-Derived Neurotrophic Factor; D015816:Cell Adhesion Molecules, Neuronal; D016326:Extracellular Matrix Proteins; C497394:Mecp2 protein, rat; D008738:Methyl Ethers; D051783:Methyl-CpG-Binding Protein 2; D009419:Nerve Tissue Proteins; D012333:RNA, Messenger; D000091042:Reelin Protein; C000717129:Reln protein, rat; D000077149:Sevoflurane; D000077209:Decitabine; D015254:DNA Modification Methylases; D012697:Serine Endopeptidases; D001374:Azacitidine
keywords: Cognition; DNA methylation; Neurotoxicity; Sevoflurane