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

Biomed Pharmacother. 2018 Oct:106:1250-1257. doi: 10.1016/j.biopha.2018.07.063. Epub 2018 Jul 20.

Abstract

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.

Keywords: Cognitive impairment; Formononetin; HMGB1/TLR4/NF-κB signaling; NLRP3 inflammasome; STZ.

MeSH terms

  • 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
  • Diabetes Mellitus, Experimental / blood
  • Diabetes Mellitus, Experimental / chemically induced
  • Diabetes Mellitus, Experimental / drug therapy*
  • Dose-Response Relationship, Drug
  • HMGB1 Protein / metabolism
  • Hippocampus / drug effects*
  • Hippocampus / metabolism
  • Hippocampus / physiopathology
  • 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
  • NF-kappa B / metabolism
  • NLR Family, Pyrin Domain-Containing 3 Protein / metabolism
  • Neurons / drug effects
  • Neurons / metabolism
  • Signal Transduction / drug effects
  • Streptozocin*
  • Toll-Like Receptor 4 / metabolism
  • Weight Loss / drug effects

Substances

  • Blood Glucose
  • HMGB1 Protein
  • HMGB1 protein, mouse
  • Hypoglycemic Agents
  • Inflammasomes
  • Inflammation Mediators
  • Isoflavones
  • NF-kappa B
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Nlrp3 protein, mouse
  • Tlr4 protein, mouse
  • Toll-Like Receptor 4
  • formononetin
  • Streptozocin
  • Metformin