Article

Molecular Neurobiology

, Volume 50, Issue 3, pp 937-944

Epigenetic Enhancement of Brain-Derived Neurotrophic Factor Signaling Pathway Improves Cognitive Impairments Induced by Isoflurane Exposure in Aged Rats

  • MuHuo JiAffiliated withDepartment of Anesthesiology, Jinling Hospital, School of Medicine, Nanjing University
  • , Lin DongAffiliated withDepartment of Anesthesiology, Jinling Hospital, School of Medicine, Nanjing University
  • , Min JiaAffiliated withDepartment of Anesthesiology, Jinling Hospital, School of Medicine, Nanjing University
  • , WenXue LiuAffiliated withDepartment of Anesthesiology, Jinling Hospital, School of Medicine, Nanjing University
  • , MingQiang ZhangAffiliated withDepartment of Anesthesiology, Jinling Hospital, School of Medicine, Nanjing University
  • , LinSha JuAffiliated withDepartment of Anesthesiology, Jinling Hospital, School of Medicine, Nanjing University
  • , JiaoJiao YangAffiliated withDepartment of Anesthesiology, Jinling Hospital, School of Medicine, Nanjing University
  • , Zhongcong XieAffiliated withGeriatric Anesthesia Research Unit, Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital and Harvard Medical School
  • , JianJun YangAffiliated withDepartment of Anesthesiology, Jinling Hospital, School of Medicine, Nanjing University Email author 

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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.

Keywords

Cognition Histone acetylation Brain-derived neurotrophic factor Inflammation Apoptosis