title: Epigenetic enhancement of brain-derived neurotrophic factor signaling pathway improves cognitive impairments induced by isoflurane exposure in aged rats.
abstract: Isoflurane-induced cognitive impairments are well documented in animal models; yet, the molecular mechanisms remain largely to be determined. In the present study, 22-month-old male Sprague-Dawley rats received 2 h of 1.5 % isoflurane or 100 % oxygen daily for 3 consecutive days. For the intervention study, the rats were intraperitoneally injected with 1.2 g/kg sodium butyrate 2 h before isoflurane exposure. Our data showed that repeated isoflurane exposure significantly decreased the freezing time to context and the freezing time to tone in the fear conditioning test, which was associated with upregulated histone deacetylase 2, reduced histone acetylation, and increased inflammation and apoptosis in the hippocampus, and impairments of brain-derived neurotrophic factor (BDNF)-tyrosine kinase receptor B (TrkB) and the downstream signaling pathway phospho-calmodulin-dependent protein kinase and phospho-cAMP response element-binding protein. These results suggest that isoflurane-induced cognitive impairments are associated with the declines in chromatin histone acetylation and the resulting downregulation of BDNF-TrkB signaling pathway. Moreover, the cognitive impairments and the signaling deficits can be rescued by histone deacetylase inhibitor sodium butyrate. Therefore, epigenetic enhancement of BDNF-TrkB signaling may be a promising strategy for reversing isoflurane-induced cognitive impairments.
authors.affiliation: Department of Anesthesiology, Jinling Hospital, School of Medicine, Nanjing University, Nanjing, China.
authors.forename: MuHuo
authors.initials: M
authors.lastname: Ji
authors.forename: Lin
authors.initials: L
authors.lastname: Dong
authors.forename: Min
authors.initials: M
authors.lastname: Jia
authors.forename: WenXue
authors.initials: W
authors.lastname: Liu
authors.forename: MingQiang
authors.initials: M
authors.lastname: Zhang
authors.forename: LinSha
authors.initials: L
authors.lastname: Ju
authors.forename: JiaoJiao
authors.initials: J
authors.lastname: Yang
authors.forename: Zhongcong
authors.initials: Z
authors.lastname: Xie
authors.forename: JianJun
authors.initials: J
authors.lastname: Yang
mesh_terms: D000375:Aging / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001245:Association Learning / Q000502:physiology; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism*; D003072:Cognition Disorders / Q000139:chemically induced / Q000235:genetics* / Q000378:metabolism; D003214:Conditioning, Classical / Q000502:physiology; D044127:Epigenesis, Genetic; D005239:Fear; D006624:Hippocampus / Q000378:metabolism*; D007530:Isoflurane; D008297:Male; D010766:Phosphorylation; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000235:genetics*
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D007530:Isoflurane