Molecular Neurobiology

, Volume 50, Issue 3, pp 937–944 | Cite as

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

  • MuHuo Ji
  • Lin Dong
  • Min Jia
  • WenXue Liu
  • MingQiang Zhang
  • LinSha Ju
  • JiaoJiao Yang
  • Zhongcong Xie
  • JianJun Yang


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.


Cognition Histone acetylation Brain-derived neurotrophic factor Inflammation Apoptosis 


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Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • MuHuo Ji
    • 1
  • Lin Dong
    • 1
  • Min Jia
    • 1
  • WenXue Liu
    • 1
  • MingQiang Zhang
    • 1
  • LinSha Ju
    • 1
  • JiaoJiao Yang
    • 1
  • Zhongcong Xie
    • 2
  • JianJun Yang
    • 1
  1. 1.Department of Anesthesiology, Jinling Hospital, School of MedicineNanjing UniversityNanjingChina
  2. 2.Geriatric Anesthesia Research Unit, Department of Anesthesia, Critical Care and Pain MedicineMassachusetts General Hospital and Harvard Medical SchoolCharlestownUSA

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