Diabetic cognitive impairment (DCI) is a common complication of diabetes characterized by loss of learning ability, memory, and behavioral impairments that severely worsen a patient's quality of life. Diabetes mellitus (DM) is a global epidemic that affects more than 422 million people worldwide, 30% of whom have DCI, a higher risk of Alzheimer's disease (AD) than the general population, and currently available treatments remain extremely limited.
Glucocorticoid receptor (GR) dysfunction is the leading cause of neuronal dysfunction in the brain of diabetics.
Image source: https://pubmed.ncbi.nlm.nih.gov/35172041/
Recently, researchers from the Jiangsu Key Laboratory of Pharmacology and Safety Evaluation of Traditional Chinese Medicine and the School of Medicine and Integral Integration of Nanjing University of Traditional Chinese Medicine published a non-steroidal glucocorticoid receptorantagonist ameliorates diabetic cognitive impairment in the journal Agging Cell MICE article "Epoflavones as nonsteroidal glucocorticoid receptor antagonists improve cognitive dysfunction in diabetic mice", the study for the first time elucidated the detailed mechanism of NSAIDs to improve DCI-like pathology in mice, and reported the potential of epflavones (IP) in DCI therapy.
First, this study found that ippriflavone (IP) as a nonsteroidal GR antagonist can effectively improve learning and memory dysfunction in mice with type 1 and type 2 diabetes. The researchers conducted in-depth research into the underlying mechanisms of diabetic mice that inhibit GR in the brain by injecting adeno-associated virus (AAV)-epphp-si-GR.
In terms of mechanism, the researchers found that IP inhibits hyperphosphorylation of tau through the GR/PI3K/AKT/GSK3β pathway, relieves neuronal inflammation through the GR/NF-κB/NLRP3/ASC/Caspase-1 pathway, and protects synapses from damage through the GR/CREB/BDNF pathway.
IP inhibits neuroinflammation in diabetic mice by GR/NF-κB/NLRP3/ASC/Caspase-1
In summary, IP as a nonsteroidal GR antagonist effectively improves DCI in mice. The mechanism is to inhibit tau hyperphosphorylation through the GR/PI3K/AKT/GSK3β pathway, reduce neuronal inflammation through the GR/NF-κB/NLRP3/ASC/Caspase-1 pathway, and improve synaptic damage through the GR/CREB/BDNF pathway. Overall, the study's work focused on the potential of NSAIDs in the treatment of DCIs and highlighted the potential of IP in the treatment of this disease.
bibliography:
Ruifang Nie et al. Ipriflavone as a non-steroidal glucocorticoid receptor antagonist ameliorates diabetic cognitive impairment in mice. Aging Cell. 2022 Feb 16;e13572. doi: 10.1111/acel.13572.