Ipriflavone as a non‐steroidal glucocorticoid receptor antagonist ameliorates diabetic cognitive impairment in mice |
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Authors: | Ruifang Nie Jian Lu Rui Xu Juanzhen Yang Xingyi Shen Xingnan Ouyang Danyang Zhu Yujie Huang Tong Zhao Xuejian Zhao Yin Lu Minyi Qian Jiaying Wang Xu Shen |
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Institution: | 1. Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica and School of Medicine & Holistic Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing China |
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Abstract: | 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. |
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Keywords: | antagonist diabetes diabetic cognitive impairment glucocorticoid receptor glucocorticoids ipriflavone |
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