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【研究背景及目的】胰岛素抵抗及2型糖尿病越来越成为全球的公共问题。肥胖相关的胰岛素抵抗是2型糖尿病等多种疾病病程中的早期事件，糖尿病可以引起中枢神经炎症、神经元凋亡，降低认知功能和学习能力，导致阿尔茨海默病等神经退行性疾病。TLR4作为TLRs受体成员之一，表达于多种细胞。研究表明，TLR4参与肥胖所致外周胰岛素抵抗形成过程，但该受体所依赖的信号转导途径在2型糖尿病小鼠的海马神经炎症反应及海马CA1区神经元损伤中的作用及其机制尚不清楚。因此，我们首先建立高脂饮食联合STZ诱导的2型糖尿病模型，通过观察TLR4受体抑制剂TAK-242对2型糖尿病所致的小鼠海马炎症和海马CA1区神经元损伤的影响，从而探讨TLR4与2型糖尿病所致的小鼠海马炎症和海马CA1区神经元损伤的关系。 【方法】通过高脂饮食联合腹腔注射链脲佐菌素（STZ）建立2型糖尿病小鼠模型；通过测量小鼠体重、空腹血糖、糖耐量试验、胰岛素耐量试验观察高脂饮食联合链脲佐菌素对小鼠体重、空腹血糖、糖尿病、胰岛素耐量的影响；采用HE染观察2型糖尿病小鼠海马CA1区神经元的损伤；采用Western Blot检测2型糖尿病小鼠海马IBA-1蛋白表达水平；采用Western Blot检测2型糖尿病小鼠海马TLR4、NF-κB、IL-1β蛋白表达水平；通过测量体重及空腹血糖，观察TAK-242对2型糖尿病小鼠空腹血糖及体重的影响，以阐明TLR4与2型糖尿病小鼠空腹血糖及体重的关系；通过HE染观察TAK-242 I
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对2型糖尿病小鼠海马CA1区神经元损伤的影响，从而探讨TLR4与2型糖尿病小鼠海马CA1区神经元损伤的关系；采用Western Blot 检测方法观察TAK-242对2型糖尿病小鼠海马IBA-1蛋白表达水平的影响，探讨TLR4与2型糖尿病小鼠海马蛋白IBA-1表达水平的关系；采用Western Blot检测方法观察TAK-242对2型糖尿病小鼠海马TLR4、NF-κB、IL-1β蛋白表达水平的影响，以阐明TLR4与2型糖尿病小鼠海马NF-κB、IL-1β蛋白表达水平的关系。
【结果】由高脂饮食联合STZ诱导的小鼠出现空腹血糖升高和胰岛素抵抗，表明2型糖尿病小鼠模型建立；TAK-242可降低2型糖尿病小鼠空腹血糖；TAK-242对2型糖尿病小鼠体重无明显影响；TAK-242抑制2型糖尿病小鼠海马IBA-1蛋白表达增加；TAK-242抑制2型糖尿病小鼠海马TLR4、NF-κB、IL-1β蛋白表达增加；TAK-242对2型糖尿病小鼠海马CA1区神经元具有保护作用。
【结论】TLR4介导的信号通路参与2型糖尿病诱导的海马神经炎症及海马CA1区神经元损伤。
关键词：2型糖尿病；神经炎症；TLR4；TAK-242
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TOLL-LIKE RECEPTOR4ANTAGONIST TAK-242
AMELIORATES HIPPOCAMPAL NEUROINFLAMMATION IN TYPE2DIABETIC MICE
Abstract:
【Research background and Objective】Insulin resistance and type2diabetes are increasingly becoming a global public problem. Obesity-related insulin resistance is an early event in the course of various diseases such as type2diabetes.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 TLR4is involved in the formation of peripheral insulin resistance induced by obesity,role of TLR4in hippocampal neuroinflammation and hippocampal CA1neurons damage in type2diabetic mice is still unclear.Therefore,we first established type2diabetes model induced by high-fat diet and STZ.We then further investigate whether hippocampal inflammation and neuronal damage in hippocampal CA1region were induced in type2diabetes mice, and whether these effects are ameliorated by treatment with TLR4 receptor antagonist TAK-242.
【Methods】A mouse model of type2diabetes was established
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by high-fat diet and intraperitoneal injection of STZ.The change of body weight、fasting blood glucos
e、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 type2diabetic mice was measured by HE staining.The activation of hippocampal CA1region IBA-1in type2diabetes mouse was measured by Western blot（WB）analysis.The expression of TLR4, NF-κB and IL-1βin type2diabetes mouse was measured by WB.The effects of TAK-242on fasting blood glucose and body weight in type2 diabetic 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 type2diabetic mice.HE staining was used to observe the effect of TAK-242on neuronal damage in hippocampal CA1region of type2diabetic mice,for discussion the relationship between TLR4and neuronal damage in hippocampal CA1 region of type2diabetic mice.The effect of TAK-242on expressions of hippocampal IBA-1protein in type2diabetic mice were measured by WB,To Investigate the relationship between TLR4and IBA-1protein expression level in type2diabetic mice.The effect of TAK-242on expressions of hippocampal TLR4,NF-κB and IL-1βprotein in type2 diabetic mice were measured by WB,To Investigate the relationship IV
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between TLR4and NF-κB and IL-1βprotein expression level in type2 diabetic mice.
【Results】A mouse model of type2diabetes was built, indicated by significantly elevated fasting blood glucose levels and insulin resistance.Fasting blood glucose was reduced by TAK-242in type2diabetic mice.There was no significant effect on body weight of TAK-242of type2diabetic mice.The increased of IBA-1in hippocampus of type2diabetic mice was ameliorated by TAK-242 treatment.With the decrease in expression of IBA-1in hippocampus of type2diabetic mice,the expression of TLR4,NF-κB and IL-1βin hippocampus of type2diabetic mice was profoundly lowered by TAK-242administration,respectively.Furthermore,Treatment with TAK-242protected from hippocampal CA1neuronal damage in type2 diabetic mice.
【Conclusion】TLR4-mediated pathways are involved in hippocampal neuroinflammation and hippocampal CA1neuronal damage in type2diabetic mice.
绝缘软母排
Keywords:Type2diabetes neuroinflammation TLR4TAK-242
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