代谢性谷氨酸受体5变构调节剂对β淀粉样蛋白寡聚体引起细胞毒性影响的研究  

Effect of mGluR5 allosteric modulators on amyloid β oligomers-induced cytotoxicity

作　　者：孙永安[1] 褚文正[2] 金海强[1] 叶长青[1] 衷弘熙[1] 徐俊[3] 暴党振[1] 都爱莲[4] 

机构地区：[1]北京大学第一医院神经内科,100034 [2]烟台毓璜顶医院神经内科 [3]江苏省苏北人民医院神经内科 [4]上海交通大学附属同仁医院神经内科

出　　处：《中华老年心脑血管病杂志》2016年第11期1199-1203,共5页Chinese Journal of Geriatric Heart,Brain and Vessel Diseases

基　　金：北京大学第一医院留学归国基金资助项目(2015GG006)

摘　　要：目的研究代谢性谷氨酸受体5(mGluR5)变构调节剂对细胞型朊蛋白(PrPc)免疫共沉淀效应的影响,筛选能有效阻断β淀粉样蛋白寡聚体(Aβo)细胞毒性信号化合物。方法人胚胎肾293细胞进行培养,按照加入mGluR5变构剂的不同,随机分为8组,分别为:对照组、3-[(2-甲基-4-噻唑基)乙炔基]吡啶盐酸盐(MTEP)组、6-甲基-2-(偶氮苯基)-3-羟基吡啶(SIB)组、S-(4-氟苯基)-{3-[3-(4-氟苯基)-5-(1,2,4)-恶二唑基]-1-哌啶基}-甲酮(ADX-47273)组、二羟基苯基甘氨酸(DHPG)组、6-甲氧基-N-(4-甲氧基苯基)-4-喹唑啉铵盐酸盐(LY-456236)组、4-丁氧基-N-(2,4-二氟苯基)苯甲酰胺(VU-0357121)组、3,3-二氯二苯甲醛双腙(DCB)组,利用转基因技术及免疫共沉淀技术,研究上述不同的mGluR5变构调节剂对PrPc和mGluR5的免疫共沉淀的影响。结果 MTEP组、SIB组的PrPc(30.87±2.65、40.25±3.21 vs 100.00±0.00,P<0.05)和mGluR5(30.12±4.23、51.67±7.09 vs100.00±0.00,P<0.05,P<0.01)免疫共沉淀较对照组均明显减少(P<0.01),其中MTEP对免疫共沉淀的抑制最强。ADX-47273组、DHPG组、LY-456236组和VU-0357121组的PrPc和mGluR5免疫共沉淀较对照组均明显增加,其中DHPG组对免疫共沉淀信号增强效应最强。结论负性变构调节剂MTEP能减弱Aβo的细胞毒性信号向细胞内传递,可能为阿尔茨海默病治疗的药物。Objective To study the effect of allosteric modulators on co-immunoprecipitation of cellular prion protein（PrPc）and identify the compounds that can effectively block the cytotoxicity signals of amyloid-βoligomers（Aβo）.Methods The cultured human embryonic kidney 293 cells were divided into control group,MTEP group,SIB group,ADX-47273 group,DHPG group,LY-456236 group,VU-0357121 group and DCB group.The effect of mGluR5 allosteric modulators on co-immunoprecipitation of PrPc and mGluR5 was detected by transgenic technology and co-immunoprecipitation technology respectively.Results The effect of allosteric modulators on co-immunoprecipitation of PrPc and mGluR5 was significantly lower in MTEP group and SIB group than in control group（30.87±2.65 vs 100.00±0.00,40.25±3.21 vs 100.00±0.00,P〈0.05and30.12±4.23 vs 100.00±0.00,P〈0.01,51.67±7.09 vs 100.00±0.00,P〈0.05）and was significantly higher in ADX-47273 group,DHPG group,LY-456236 group,VU-0357121 group than in control group（P〈0.01,P〈0.05）.Conclusion MTEP can reduce the transmission of cytotoxicity signals of Aβo into cells and can thus be used as a drug in treatment of AD.

关 键 词：受体 谷氨酸 淀粉样Β蛋白 免疫沉淀法 阿尔茨海默病 

分 类 号：R749.16[医药卫生—神经病学与精神病学]