典型文献
FX5,a non-steroidal glucocorticoid receptor antagonist,ameliorates diabetic cognitive impairment in mice
文献摘要：
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 T1 DM 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-KB/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.
文献关键词：
中图分类号：
作者姓名：
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
作者机构：
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;Faculty of Art and Science,Queens University,Kingston,ON K7L 3N6,Canada
文献出处：
引用格式：
[1]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-.FX5,a non-steroidal glucocorticoid receptor antagonist,ameliorates diabetic cognitive impairment in mice)[J].中国药理学报（英文版）,2022(10):2495-2510
A类：
FX5,tauopathy
B类：
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AB值：
0.526635
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