RAGE阻断剂FPS-ZM1对糖基化终末产物所致大鼠脑部炎症反应的影响及机制  

Effects of RAGE inhibitor FPS-ZM1 on inflammatory reaction in the brain of rats induced by advanced glycation end products

作　　者：孙梦晗[1] 洪艳[1] 候训尧 马莹娟 申超[1] 罗鼎真[1] 刘雪平[1] 

机构地区：[1]山东大学附属省立医院老年神经科,山东济南250021

出　　处：《中国老年学杂志》2014年第10期2752-2755,共4页Chinese Journal of Gerontology

基　　金：国家自然科学基金(No.30971036)

摘　　要：目的探讨RAGE受体特异性阻断剂FPS-ZM1对糖基化终末产物(AGEs)所致大鼠脑部炎症反应及认知功能的影响。方法将40只大鼠随机分为四组:生理盐水组(NC组)FPS-ZM1对照组、AGEs组和FPS-ZM1组,采用脑立体定位技术,向AGEs组及FPS-ZM1组大鼠两侧海马注射AGEs 5μl,以制造动物损伤模型,用同样方法向NC组及FPS-ZM1对照组注射等量生理盐水,以制造模型对照;造模前1 w以1 mg·kg-1·d-1FPS-ZM1向FPS-ZM1组和FPS-ZM1对照组大鼠进行腹腔注射,并连续4 w给药,AGEs组、NC组则同时注射相同体积生理盐水,造模3 w后对各组大鼠进行Morris水迷宫实验,检测各组大鼠逃逸潜伏期(EL);用Elisa检测各组大鼠海马区Aβ1~40,Aβ1~42的水平;用Western印迹检测各组大鼠RAGE,p-NF-κB和肿瘤坏死因子(TNF)-α蛋白的表达;用免疫组织化学法检测各组大鼠海马区TNF-α蛋白的表达强度。结果 AGEs组与其他各组相比,EL显著延长(P【0.01),且Aβ1~40、Aβ1~42浓度均显著升高(P【0.01);同时AGEs组RAGE、p-NF-κB和TNF-α的蛋白表达明显增强(P【0.01);FPS-ZM1干预后上述各指标均明显低于AGEs组。结论 FPS-ZM1作为RAGE受体特异性阻断剂,能作用中枢系统减少Aβ1~40,生成从而提高AGEs脑损伤大鼠的智能,并通过抑制脑组织p-NF-κB上调,减轻脑AGEs损伤引起的炎性反应。该药因能透过血脑屏障有望成为抑制阿尔茨海默样病变的有效措施。Objective To explore the effects of RAGE inhibitor FPS-ZM1 on inhibiting inflammatory reaction in the brain of rats and cognition induced by advanced glycation end products.Methods Fourty Wistar rats were randomly divided into normal control ( NC) , FPS-ZM1 control , AGEs and FPS-ZM1 groups.By brain stereotactic techniques , the bilateral hippocampus of rats in AGEs group and FPS-ZM1 group were injected AGEs to make injuring models ,NC group and FPS-ZM1 group were injected equal volume of saline in the same way to make control model.Rats in FPS-ZM1 control and FPS-ZM1 groups were injected FPS-ZM1 1 mg· kg-1 · d-1 for 4 weeks before the animal models were produced , rats in AGEs and NC groups were injected equal volume of saline intraabdominally at the same time.After construc-ting the animal model for 3 weeks, the escape latency (EL) of rats in each group was assayed with Morris water maze test;ELISA was used to measure the level of Aβ1~40 , Aβ1~42 in hippocampus of all groups;Western blot was performed to detect the expressions of RAGE , p-NF-κB and TNFαprotein in rat hippocampus.The brain sections were stained by immunohistochemistry to examine the expression of TNFαin hippocampus of the rats.Results Comparing AGEs group with other groups , the EL was also longer(P<0.01).Meanwhile,compared with those of NC group , the concentrations of Aβ1~40 , Aβ1~42 in the hippocampus of AGEs group were obviously increased ( P<0.01 ) and the protein expressions of RAGE , p-NF-κB and TNFαwere significantly higher in AGEs group ( P<0.01 ).After the intervention of FPS-ZM1, each index was evidently lower than that of AGEs group.Conclusions FPS-ZM1,as the specific inhibitor of RAGE , could effectively sup-press the upregulation of p-NF-κB to restrain the inflammatory reaction in the brain of rats induced by advanced glycation end products and enhance cognition of the rats.FPS-ZM1 might become a valid measurement to control Alzheimer ’ s disease.

关 键 词：高级糖基化终末产物受体 阿尔茨海默病 FPS-ZM1 p-NF-κB AΒ 

分 类 号：R363[医药卫生—病理学]