Toll-Like Receptor 4 Antagonist TAK-242 Ameliorates Hippocampal Neuroinflammation In Type 2 Diabetic Mice

?Research background and Objective? Insulin resistance and type 2 diabetes are increasingly becoming a global public problem.Obesity-related insulin resistance is an early event in the course of various diseases such as type 2 diabetes.Diabetes can cause neuroinflammation,neuronal apoptosis,reduce cognitive function and learning ability,and incur neurodegenerative diseases such as Alzheimer's disease.TLR4,a member of TLRs receptors,is expressed in a variety of cells.Although studies have shown that TLR4 is involved in the formation of peripheral insulin resistance induced by obesity,role of TLR4 in hippocampal neuroinflammation and hippocampal CA1 neurons damage in type 2 diabetic mice is still unclear.Therefore,we first established type 2 diabetes model induced by high-fat diet and STZ.We then further investigate whether hippocampal inflammation and neuronal damage in hippocampal CA1 region were induced in type 2 diabetes mice,and whether these effects are ameliorated by treatment with TLR4 receptor antagonist TAK-242.?Methods?A mouse model of type 2 diabetes was establishedby high-fat diet and intraperitoneal injection of STZ.The change of body weight ? fasting blood glucose ? glucose tolerance of mice and insulin tolerance test treated with high-fat diet and STZ were observed by measuring mouse body weight?fasting blood glucose?glucose tolerance test and insulin tolerance test.Neuronal damage in hippocampal CA1 region of type 2 diabetic mice was measured by HE staining.The activation of hippocampal CA1 region IBA-1 in type 2 diabetes mouse was measured by Western blot(WB)analysis.The expression of TLR4,NF-?B and IL-1? in type 2 diabetes mouse was measured by WB.The effects of TAK-242 on fasting blood glucose and body weight in type 2diabetic mice were observed by measuring changes in fasting blood glucose and body weight,To elucidate the relationship between TLR4 and fasting blood glucose and body weight in type 2 diabetic mice.HE staining was used to observe the effect of TAK-242 on neuronal damage in hippocampal CA1 region of type 2 diabetic mice,for discussion the relationship between TLR4 and neuronal damage in hippocampal CA1 region of type 2 diabetic mice.The effect of TAK-242 on expressions of hippocampal IBA-1 protein in type 2 diabetic mice were measured by WB,To Investigate the relationship between TLR4 and IBA-1 protein expression level in type 2 diabetic mice.The effect of TAK-242 on expressions of hippocampal TLR4,NF-?B and IL-1? protein in type 2diabetic mice were measured by WB,To Investigate the relationshipbetween TLR4 and NF-?B and IL-1? protein expression level in type 2diabetic mice.?Results? A mouse model of type 2 diabetes was built,indicated by significantly elevated fasting blood glucose levels and insulin resistance.Fasting blood glucose was reduced by TAK-242 in type 2 diabetic mice.There was no significant effect on body weight of TAK-242 of type 2 diabetic mice.The increased of IBA-1 in hippocampus of type 2 diabetic mice was ameliorated by TAK-242 treatment.With the decrease in expression of IBA-1 in hippocampus of type 2 diabetic mice,the expression of TLR4,NF-?B and IL-1? in hippocampus of type 2 diabetic mice was profoundly lowered by TAK-242 administration,respectively.Furthermore,Treatment with TAK-242 protected from hippocampal CA1 neuronal damage in type 2diabetic mice.?Conclusion? TLR4-mediated pathways are involved in hippocampal neuroinflammation and hippocampal CA1 neuronal damage in type 2 diabetic mice.