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

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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.

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Acknowledgments

The authors declare no conflict of interest. This work was supported by the National Natural Science Foundation of China (no. 81271216 and 81300946) and the Natural Science Foundation of Jiangsu Province (no. BK2012778).

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Authors and Affiliations

  1. Department of Anesthesiology, Jinling Hospital, School of Medicine, Nanjing University, Nanjing, China

    MuHuo Ji, Lin Dong, Min Jia, WenXue Liu, MingQiang Zhang, LinSha Ju, JiaoJiao Yang & JianJun Yang

  2. Geriatric Anesthesia Research Unit, Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, 02129-2060, USA

    Zhongcong Xie

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  1. MuHuo Ji
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Correspondence to JianJun Yang.

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Ji, M., Dong, L., Jia, M. et al. Epigenetic Enhancement of Brain-Derived Neurotrophic Factor Signaling Pathway Improves Cognitive Impairments Induced by Isoflurane Exposure in Aged Rats. Mol Neurobiol 50, 937–944 (2014). https://doi.org/10.1007/s12035-014-8659-z

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