title: Enhanced neuroinflammation mediated by DNA methylation of the glucocorticoid receptor triggers cognitive dysfunction after sevoflurane anesthesia in adult rats subjected to maternal separation during the neonatal period.
abstract: Mounting evidence indicates that children who experience abuse and neglect are prone to chronic diseases and premature mortality later in life. One mechanistic hypothesis for this phenomenon is that early life adversity alters the expression or functioning of the glucocorticoid receptor (GR) throughout the course of life and thereby increases sensitivity to inflammatory stimulation. An exaggerated pro-inflammatory response is generally considered to be a key cause of postoperative cognitive dysfunction (POCD). The aim of this study was to examine the effects of early life adversity on cognitive function and neuroinflammation after sevoflurane anesthesia in adult rats and to determine whether such effects are associated with the epigenetic regulation of GR.
  
  
  
  Wistar rat pups were repeatedly subjected to infant maternal separation (early life stress) from postnatal days 2-21. In adulthood, their behavior and the signaling of hippocampal pro-inflammatory factors and nuclear factor-kappa B (NF-κB) after sevoflurane anesthesia were evaluated. We also examined the effects of maternal separation (MS) on the expression of GR and the DNA methylation status of the promoter region of exon 17of GR and whether behavioral changes and neuroinflammation after anesthesia were reversible when the expression of GR was increased by altering DNA methylation.
  
  
  
  MS induced cognitive decline after sevoflurane inhalation in the Morris water maze and context fear conditioning tests and enhanced the release of cytokines and the activation of astrocyte intracellular NF-κB signaling induced by sevoflurane in the hippocampus of adult rats. Blocking NF-κB signaling by pyrrolidine dithiocarbamate (PDTC) inhibited the release of cytokines. MS also reduced the expression of GR and upregulated the methylation levels of the promoter region of GR exon 17, and such effects were reversed by treatment with the histone deacetylase inhibitor trichostatin A (TSA) in adult rats. Moreover, TSA treatment in adult MS rats inhibited the overactivation of astrocyte intracellular NF-κB signaling and the release of cytokines and alleviated cognitive dysfunction after sevoflurane anesthesia.
  
  
  
  Early life stress induces cognitive dysfunction after sevoflurane anesthesia, perhaps due to the aberrant methylation of the GR gene promoter, which reduces the expression of the GR gene and facilitates exaggerated inflammatory responses.
authors.affiliation: Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou Medical University, 209 Tongshan, Xuzhou, 221004, People's Republic of China.|Department of Anesthesiology, Xuzhou Central Hospital, 199 Jiefang South Road, Xuzhou, People's Republic of China.
authors.forename: Yangzi
authors.initials: Y
authors.lastname: Zhu
authors.affiliation: Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou Medical University, 209 Tongshan, Xuzhou, 221004, People's Republic of China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou Medical University, 209 Tongshan, Xuzhou, 221004, People's Republic of China.
authors.forename: Rui
authors.initials: R
authors.lastname: Yao
authors.affiliation: Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou Medical University, 209 Tongshan, Xuzhou, 221004, People's Republic of China.
authors.forename: Ting
authors.initials: T
authors.lastname: Hao
authors.affiliation: Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou Medical University, 209 Tongshan, Xuzhou, 221004, People's Republic of China.
authors.forename: Junli
authors.initials: J
authors.lastname: Cao
authors.affiliation: Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou Medical University, 209 Tongshan, Xuzhou, 221004, People's Republic of China.
authors.forename: He
authors.initials: H
authors.lastname: Huang
authors.affiliation: Department of Anesthesiology, Xuzhou Central Hospital, 199 Jiefang South Road, Xuzhou, People's Republic of China. doctorlww@sina.com.
authors.forename: Liwei
authors.initials: L
authors.lastname: Wang
authors.affiliation: Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou Medical University, 209 Tongshan, Xuzhou, 221004, People's Republic of China. xzmcyqwu@sina.com.|Department of Anesthetic Pharmacology, Xuzhou Medical University, Xuzhou, People's Republic of China. xzmcyqwu@sina.com.
authors.forename: Yuqing
authors.initials: Y
authors.lastname: Wu
mesh_terms: D018685:Anesthetics, Inhalation / Q000633:toxicity*; D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism; D003072:Cognition Disorders / Q000139:chemically induced / Q000378:metabolism / Q000523:psychology; D003213:Conditioning, Psychological / Q000187:drug effects; D016207:Cytokines / Q000378:metabolism; D019175:DNA Methylation / Q000187:drug effects*; D004660:Encephalitis / Q000209:etiology* / Q000473:pathology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005239:Fear / Q000187:drug effects / Q000523:psychology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008426:Maternal Deprivation; D018782:Maze Learning / Q000187:drug effects; D008738:Methyl Ethers / Q000633:toxicity*; D016328:NF-kappa B / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D011965:Receptors, Glucocorticoid / Q000235:genetics / Q000378:metabolism*; D000077149:Sevoflurane; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D018685:Anesthetics, Inhalation; D016207:Cytokines; D004791:Enzyme Inhibitors; D005904:Glial Fibrillary Acidic Protein; D008738:Methyl Ethers; D016328:NF-kappa B; D011965:Receptors, Glucocorticoid; D000077149:Sevoflurane
keywords: Cognitive dysfunction; DNA methylation; Glucocorticoid receptor; Neuroinflammation; Pro-inflammatory factors; Sevoflurane