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Hypermethylation of Hippocampal Synaptic Plasticity-Related genes is Involved in Neonatal Sevoflurane Exposure-Induced Cognitive Impairments in Rats.
Neurotox Res. 2016 Feb; 29(2):243-55.NR

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+Show Affiliations

Department of Anesthesiology, Jinling Hospital, School of Medicine, Nanjing University, Nanjing, China.Department of Anesthesiology, Jinling Hospital, School of Medicine, Nanjing University, Nanjing, China.Department of Anesthesiology, First Affiliated Hospital of Nanjing Medical University, Nanjing, China.Department of Anesthesiology, Jinling Hospital, School of Medicine, Nanjing University, Nanjing, China.Department of Anesthesiology, Jinling Hospital, School of Medicine, Nanjing University, Nanjing, China.Department of Anesthesiology, Jinling Hospital, School of Medicine, Nanjing University, Nanjing, China.Department of Anesthesiology, Jinling Hospital, School of Medicine, Nanjing University, Nanjing, China.Department of Anesthesiology, First Affiliated Hospital of Nanjing Medical University, Nanjing, China. zywang1970@126.com.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

26678494

Citation

Ju, Ling-sha, et al. "Hypermethylation of Hippocampal Synaptic Plasticity-Related Genes Is Involved in Neonatal Sevoflurane Exposure-Induced Cognitive Impairments in Rats." Neurotoxicity Research, vol. 29, no. 2, 2016, pp. 243-55.
Ju LS, Jia M, Sun J, et al. Hypermethylation of Hippocampal Synaptic Plasticity-Related genes is Involved in Neonatal Sevoflurane Exposure-Induced Cognitive Impairments in Rats. Neurotox Res. 2016;29(2):243-55.
Ju, L. S., Jia, M., Sun, J., Sun, X. R., Zhang, H., Ji, M. H., Yang, J. J., & Wang, Z. Y. (2016). Hypermethylation of Hippocampal Synaptic Plasticity-Related genes is Involved in Neonatal Sevoflurane Exposure-Induced Cognitive Impairments in Rats. Neurotoxicity Research, 29(2), 243-55. https://doi.org/10.1007/s12640-015-9585-1
Ju LS, et al. Hypermethylation of Hippocampal Synaptic Plasticity-Related Genes Is Involved in Neonatal Sevoflurane Exposure-Induced Cognitive Impairments in Rats. Neurotox Res. 2016;29(2):243-55. PubMed PMID: 26678494.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Hypermethylation of Hippocampal Synaptic Plasticity-Related genes is Involved in Neonatal Sevoflurane Exposure-Induced Cognitive Impairments in Rats. AU - Ju,Ling-sha, AU - Jia,Min, AU - Sun,Jie, AU - Sun,Xiao-ru, AU - Zhang,Hui, AU - Ji,Mu-huo, AU - Yang,Jian-jun, AU - Wang,Zhong-yun, Y1 - 2015/12/17/ PY - 2015/07/12/received PY - 2015/12/06/accepted PY - 2015/11/24/revised PY - 2015/12/19/entrez PY - 2015/12/19/pubmed PY - 2016/10/16/medline KW - Cognition KW - DNA methylation KW - Neurotoxicity KW - Sevoflurane SP - 243 EP - 55 JF - Neurotoxicity research JO - Neurotox Res VL - 29 IS - 2 N2 - 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. SN - 1476-3524 UR - https://www.unboundmedicine.com/medline/citation/26678494/Hypermethylation_of_Hippocampal_Synaptic_Plasticity_Related_genes_is_Involved_in_Neonatal_Sevoflurane_Exposure_Induced_Cognitive_Impairments_in_Rats_ L2 - https://dx.doi.org/10.1007/s12640-015-9585-1 DB - PRIME DP - Unbound Medicine ER -