GPR30激动剂对Aβ_(1-42)所致认知功能障碍的治疗作用及其机制研究  

Therapeutic effect and mechanism of GPR30 agonist on Aβ_(1-42)-induced cognitive dysfunction

作　　者：吕扬歌 吴凌智 LYU Yangge;WU Lingzhi(Department of Pharmacy,the First Hospital of Jiaxing,the Affiliated Hospital of Jiaxing University,Zhejiang,Jiaxing 314000,China)

机构地区：[1]嘉兴市第一医院(嘉兴学院附属医院)药学部,浙江嘉兴314000

出　　处：《中国现代医生》2022年第31期15-20,共6页China Modern Doctor

基　　金：浙江省基础公益研究计划(LGD21H310003);浙江省嘉兴市医学重点学科建设计划(扶持学科-临床药学)(2019-fc-02)。

摘　　要：目的探讨G蛋白耦联受体30(G protein coupled receptor 30,GPR30)激动剂对β淀粉样蛋白(amyloidβ-protein,Aβ)_(1-42)所致小鼠认知功能障碍的治疗作用。方法将72只ICR小鼠随机分为对照组、模型组、阳性对照组、G1低剂量组、G1中剂量组和G1高剂量组。采用双侧海马脑立体定位注射Aβ_(1-42)建立阿尔茨海默病认知功能障碍模型,48h后给予GPR30激动剂G1(1mg/kg、2mg/kg、4mg/kg)。进行Morris水迷宫实验、避暗实验和新物体识别实验测试小鼠的认知能力,采用蛋白质印迹法检测小鼠海马组织中Bcl-2、Bax、caspase-3、脑源性神经营养因子(brain-derived neurotrophic factor,BDNF)、cAMP效应元件结合蛋白(cAMP response element binding protein,CREB)、p-CREB的表达水平。结果Morris水迷宫实验中,G1高剂量组小鼠的目标象限停留时间百分比和穿越平台次数显著高于模型组(P<0.05);避暗实验中,G1中、高剂量组小鼠的错误次数均显著少于模型组(P<0.05),避暗潜伏期均显著长于模型组(P<0.05);新物体识别实验中,G1中、高剂量组小鼠的识别指数均显著高于模型组(P<0.05)。G1高剂量组小鼠海马组织中的p-CREB/CREB、mBDNF/proBDNF、Bcl-2/Bax的比例显著高于模型组(P<0.05),活化的caspase-3/pro-caspase-3的比例显著低于模型组(P<0.05)。结论GPR30激动剂可通过激活CREB/BDNF通路对Aβ_(1-42)诱导的小鼠认知障碍和神经元凋亡产生保护作用。Objective To investigate the therapeutic effect of G protein coupled receptor 30(GPR30)on the cognitive function induced by amyloidβ-protein(Aβ)_(1-42) mice.Methods A total of 72 ICR mice were randomly divided into control group,model group,positive control group,G1 low-dose group,G1 medium-dose group and G1 high-dose group.Alzheimer’s disease cognitive dysfunction model was established by intrahippocampal region of mouse brain of Aβ_(1-42),48 hours later,GPR30 agonist G1(1mg/kg,2mg/kg,4mg/kg)was administered.The cognitive function of mice was assessed by Morris water maze(MWM)task,light/dark(LD)and novel object recognition(NOR)task.Western blotting was used to detect the expression of Bcl-2,Bax,caspase-3,brain-derived neurotrophic factor(BDNF),cAMP response element binding protein(CREB),and p-CREB in the hippocampus of mice.Resluts In MWM task,the percentage of dwell time in the target quadrant and times of crossing the platform in G1 high-dose group were significantly higher than those in model group(P<0.05).In LD test,the error times of mice in G1 medium-dose group and G1 high-dose group were significantly less than those in model group(P<0.05),and the latency of avoiding darkness were significantly longer than those in model group(P<0.05).In NOR task,the discrimination index of mice in G1 medium-dose group and G1 high-dose group were significantly higher than those in model group(P<0.05).The proportions of p-CREB/CREB,mBDNF/proBDNF and Bcl-2/Bax in the hippocampus of G1 high-dose group were significantly higher than those in model group(P<0.05),and the proportion of activated caspase-3/pro-caspase-3 was significantly lower than that in model group(P<0.05).Conclusion GPR30 agonist can protect against Aβ_(1-42)-induced cognitive impairment and neuronal apoptosis in mice by activating CREB/BDNF pathway.

关 键 词：G蛋白耦联受体30 阿尔茨海默病 β淀粉样蛋白_(1-42) 凋亡 神经元再生 

分 类 号：R971[医药卫生—药品]