Ipriflavone as a non‐steroidal glucocorticoid receptor antagonist ameliorates diabetic cognitive impairment in mice

• Published in: Aging cell 2022-03, Vol.21 (3), p.e13572-n/a
• Main Authors: Nie, Ruifang, Lu, Jian, Xu, Rui, Yang, Juanzhen, Shen, Xingyi, Ouyang, Xingnan, Zhu, Danyang, Huang, Yujie, Zhao, Tong, Zhao, Xuejian, Lu, Yin, Qian, Minyi, Wang, Jiaying, Shen, Xu
• Format: Article
• Language: English
• Subjects: 1-Phosphatidylinositol 3-kinase; AKT protein; Alzheimer's disease; Animals; antagonist; Brain-derived neurotrophic factor; Caspase; Cognitive ability; Cognitive Dysfunction - drug therapy; Cyclic AMP response element-binding protein; Diabetes; Diabetes mellitus; Diabetes Mellitus, Experimental - complications; Diabetes Mellitus, Experimental - drug therapy; Diabetes Mellitus, Experimental - metabolism; diabetic cognitive impairment; Estrogens; Gene expression; glucocorticoid receptor; Glucocorticoids; Humans; Hyperglycemia; Inflammation; Ipriflavone; Isoflavones; Learning; Memory; Mice; Nervous system; Osteoporosis; Pathology; Phosphatidylinositol 3-Kinases - therapeutic use; Phosphorylation; Proteins; Receptors, Glucocorticoid - metabolism; Receptors, Glucocorticoid - therapeutic use; Tau protein; Tumor necrosis factor-TNF
• ISSN: 1474-9718; 1474-9726
• DOI: 10.1111/acel.13572

Diabetic cognitive impairment (DCI) is a common diabetic complication with hallmarks of loss of learning ability and disorders of memory and behavior. Glucocorticoid receptor (GR) dysfunction is a main reason for neuronal impairment in brain of diabetic patients. Here, we determined that ipriflavone (IP) a clinical anti‐osteoporosis drug functioned as a non‐steroidal GR antagonist and efficiently ameliorated learning and memory dysfunction in both type 1 and 2 diabetic mice. The underlying mechanism has been intensively investigated by assay against the diabetic mice with GR‐specific knockdown in the brain by injection of adeno‐associated virus (AAV)‐ePHP‐si‐GR. IP suppressed tau hyperphosphorylation through GR/PI3K/AKT/GSK3β pathway, alleviated neuronal inflammation through GR/NF‐κB/NLRP3/ASC/Caspase‐1 pathway, and protected against synaptic impairment through GR/CREB/BDNF pathway. To our knowledge, our work might be the first to expound the detailed mechanism underlying the amelioration of non‐steroidal GR antagonist on DCI‐like pathology in mice and report the potential of IP in treatment of DCI. Schematic diagram illustrating the mechanism underlying the amelioration of IP as a non‐steroidal GR antagonist on diabetic cognitive impairment in mice. IP attenuated tau hyperphosphorylation through GR/PI3K/AKT/GSK3β pathway, ameliorated neuroinflammation through GR/NF‐κB/NLRP3/ASC/Caspase‐1 pathway, and protected against synaptic impairment involving GR/BDNF/TrkB/CREB pathway.