The protective effect of formononetin on cognitive impairment in streptozotocin (STZ)-induced diabetic mice

• Published in: Biomedicine & pharmacotherapy 2018-10, Vol.106, p.1250-1257
• Main Authors: Wang, Jinchun, Wang, Lei, Zhou, Jie, Qin, Aiping, Chen, Zhujing
• Format: Article
• Language: English
• Subjects: Animals; Behavior, Animal - drug effects; Blood Glucose - drug effects; Blood Glucose - metabolism; Cell Line, Tumor; Cognition - drug effects; Cognition Disorders - chemically induced; Cognition Disorders - metabolism; Cognition Disorders - prevention & control; Cognition Disorders - psychology; Cognitive impairment; Diabetes Mellitus, Experimental - blood; Diabetes Mellitus, Experimental - chemically induced; Diabetes Mellitus, Experimental - drug therapy; Dose-Response Relationship, Drug; Formononetin; Hippocampus - drug effects; Hippocampus - metabolism; Hippocampus - physiopathology; HMGB1 Protein - metabolism; HMGB1/TLR4/NF-κB signaling; Humans; Hypoglycemic Agents - pharmacology; Inflammasomes - drug effects; Inflammasomes - metabolism; Inflammation Mediators - metabolism; Isoflavones - pharmacology; Male; Maze Learning - drug effects; Memory - drug effects; Metformin - pharmacology; Mice, Inbred C57BL; Neurons - drug effects; Neurons - metabolism; NF-kappa B - metabolism; NLR Family, Pyrin Domain-Containing 3 Protein - metabolism; NLRP3 inflammasome; Signal Transduction - drug effects; Streptozocin; STZ; Toll-Like Receptor 4 - metabolism; Weight Loss - drug effects
• ISSN: 0753-3322; 1950-6007
• DOI: 10.1016/j.biopha.2018.07.063

The present study was aimed to elucidate the pharmacological effect of Formononetin (FMN) treatment on STZ-induced diabetic cognitive dysfunction. The diabetic model was induced by an intraperitoneally injection of 180 mg/kg STZ. The animals were randomly divided into five groups: control group, streptozocin (STZ, 180 mg/kg) group, STZ + metformin (Met, 200 mg/kg) group, STZ + FMN (25 mg/kg) group, STZ + FMN (50 mg/kg) group. The mice were intragastrically administrated with metformin (Met, 200 mg/kg) or FMN (25, 50 mg/kg) once daily for 6 weeks. The blood glucose content and body weight were examined. Morris water maze test and Y maze test were used to evaluate the learning and memory abilities. The cognitive decline was reversed by regulating superoxide dismutase (SOD), malondialdehyde (MDA), tumor necrosis factor-a (TNF-α), interleukin(IL)-1β, IL-6 in serum and hippocampus. The protein expressions of high mobility group box-1 protein (HMGB1), toll like receptor 4 (TLR4), myeloid differentiating factor 88 (MyD88), inhibitor of NF-κB (IκBα), p-IκBα, nuclear factor kappa-B(NF-κB), p-NF-κB, NOD-like receptor 3(NLRP3), apoptosis-associated speck-like protein containing CARD(ASC) and caspase-1 were detected. Furthermore, the SH-SY5Y cells were exposed to high glucose stimulation, FMN (2.5, 5 and 10 μM) treatment, and glycyrrhizin, the selective inhibitor of HMGB1. After an incubation for 22 h, the SH-SY5Y cells were harvested for detection. As a result, FMN treatment effectively attenuated the body weight, learning and memory abilities, as well as the levels of blood glucose, SOD, MDA, TNF-α, IL-1β, IL-6. FMN administration also downregulated the protein expressions of HMGB1, TLR4, MyD88, p-IκB, p-NF-κB, NLRP3, ASC and caspase-1. The inhibition of HMGB1 by glycyrrhizin also confirmed the involvement of HMGB1/TLR4/NF-κB/NLRP3 pathway in high glucose-induced SH-SY5Y cells. In summary, the results suggested that FMN exhibited the protective effect on STZ-induced cognitive impairment possibly via the mediation of HMGB1/TLR4/NF-κB signaling and NLRP3 inflammasome.