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Surgical stress induces brain-derived neurotrophic factor reduction and postoperative cognitive dysfunction via glucocorticoid receptor phosphorylation in aged mice.

CNS neuroscience & therapeutics (2015-01-23)
Xiao-Sheng Tian, Ya-Wei Tong, Zheng-Qian Li, Lun-Xu Li, Tao Zhang, Tian-Yun Ren, Ting Zhou, He-Cheng Wang, Rui Zhan, Yang Sun, Zhao Yan, Qiu-Dian Wang, Dong-Sheng Fan, Fan-Jun Kong, Xiang-Yang Guo, Wei-Zhong Xiao, De-Hua Chui
ABSTRACT

This study explored whether surgical stress-induced glucocorticoid receptor (GR) phosphorylation is related to postoperative cognitive dysfunction (POCD) in aged individuals. Inhibition of GR activation could be an effective treatment for POCD. A laparotomy was given to C57/BL6 mice in POCD group both 20 and 6 months old. Animals in control group were treated in identical manners except for laparotomy. Cognitive function was evaluated by Morris water maze and elevated plus maze. Western blot and Elisa assay were used to detect related molecules. Mifepristone and roscovitine were treated as inhibitions of GR phosphorylation. The cognitive function was impaired, and brain-derived neurotrophic factor (BDNF) was found reduced in aged POCD group. GR translocation into nucleus and elevated GR phosphorylation were found in prefrontal cortex of aged POCD mice. Cyclin-dependent Kinase 5 (CDK5), kinase for GR phosphorylation also elevated in aged POCD mice. With GR antagonist and CDK5 inhibitor, reduction of BDNF and cognitive dysfunction in aged mice were both rescued. These results presented a mechanism that surgical stress-induced GR phosphorylation contributes to POCD in aged individuals. Inhibition of GR activation and phosphorylation might be a potential treatment target of POCD.

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