FX5,a non-steroidal glucocorticoid receptor antagonist,ameliorates diabetic cognitive impairment in mice  

作　　者：Dan-yang Zhu Jian Lu Rui Xu Juan-zhen Yang Xiang-rui Meng Xing-nan Ou-Yang Qiu-ying Yan Rui-fang Nie Tong Zhao Yi-di Chen Yin Lu Yi-nan Zhang Wen-jun Li Xu Shen 

机构地区：[1]Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica and State Key Laboratory Cultivation Base for TCM Quality and Efficacy,Nanjing University of Chinese Medicine,Nanjing 210023,China [2]Faculty of Art and Science,Queens University,Kingston,ON K7L 3N6,Canada

出　　处：《Acta Pharmacologica Sinica》2022年第10期2495-2510,共16页中国药理学报（英文版）

基　　金：This work was supported by Innovative Research Team of Six Talent Peaks Project in Jiangsu Province(grant number TD-SWYY-013);the National Natural Science Foundation for Young Scientists of China(grant number 81703806);the Natural Science Foundation for Young Scientists of Nanjing University of Chinese Medicine(grant number NZY81703806);the Open Project of Chinese Materia Medica First-Class Discipline of Nanjing University of Chinese Medicine(grant number 2020YLXK018);Postgraduate Research&Practice Innovation Program of Jiangsu Province(grant number KYCX21_1737).

摘　　要：Diabetic cognitive impairment(DCI)is a common diabetic complication characterized by learning and memory deficits.In diabetic patients,hyperactivated hypothalamic-pituitary-adrenal(HPA)axis leads to abnormal increase of glucocorticoids(GCs),which causes the damage of hippocampal neurons and cognitive impairment.In this study we investigated the cognition-improving effects of a non-steroidal glucocorticoid receptor(GR)antagonist 5-chloro-N-[4-chloro-3-(trifluoromethyl)phenyl]thiophene-2-sulfonamide(FX5)in diabetic mice.Four weeks after T1DM or T2DM was induced,the mice were administered FX5(20,40 mg·kg^(-1)·d^(-1),i.g.)for 8 weeks.Cognitive impairment was assessed in open field test,novel object recognition test,Y-maze test,and Morris water maze test.We showed that FX5 administration significantly ameliorated the cognitive impairments in both type 1 and 2 diabetic mice.Similar cognitive improvement was observed in diabetic mice following brain GR-specific knockdown by injecting AAV-si-GR.Moreover,AAV-si-GR injection occluded the cognition-improving effects of FX5,suggesting that FX5 functioning as a non-steroidal GR antagonist.In PA-treated primary neurons(as DCI model in vitro),we demonstrated that FX5(2,5,10μM)dose-dependently ameliorated synaptic impairment via upregulating GR/BDNF/TrkB/CREB pathway,protected against neuronal apoptosis through repressing GR/PI3K/AKT/GSK3β-mediated tauopathy and subsequent endoplasmic reticulum stress.In LPS-treated primary microglia,FX5 dose-dependently inhibited inflammation through GR/NF-κB/NLRP3/ASC/Caspase-1 pathway.These beneficial effects were also observed in the hippocampus of diabetic mice following FX5 administration.Collectively,we have elucidated the mechanisms underlying the beneficial effects of non-steroidal GR antagonist FX5 on DCI and highlighted the potential of FX5 in the treatment of the disease.

关 键 词：DIABETES diabetic cognitive impairment glucocorticoid receptor antagonist FX5 learning and memory HIPPOCAMPUS synaptic impairment neuronal apoptosis inflammation 

分 类 号：R285.5[医药卫生—中药学]