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

   
@article{APS10679,
	author = {Dan-yang Zhu and Jian Lu and Rui Xu and Juan-zhen Yang and Xiang-rui Meng and Xing-nan Ou-Yang and Qiu-ying Yan and Rui-fang Nie and Tong Zhao and Yi-di Chen and Yin Lu and Yi-nan Zhang and Wen-jun Li and Xu Shen},
	title = {FX5, a non-steroidal glucocorticoid receptor antagonist, ameliorates diabetic cognitive impairment in mice},
	journal = {Acta Pharmacologica Sinica},
	volume = {43},
	number = {10},
	year = {2022},
	keywords = {},
	abstract = {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, 10 μM) 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.},
	issn = {1745-7254},	url = {http://www.chinaphar.com/article/view/10679}
}