摘要
目的探究不同剂量盐酸二甲双胍对精神分裂症(SZ)模型小鼠行为和候选基因的影响,为临床治疗SZ提供新的思路和线索。方法将50只同批次C57BL/6J小鼠随机分为空白对照组、阴性对照组及盐酸二甲双胍低、中、高剂量实验组(200、400、800 mg/kg),每组10只。除空白对照组外,其他组腹腔注射谷氨酸N-甲基-D-天冬氨酸(NMDA)受体非竞争性拮抗剂地卓西平马来酸盐(MK-801)建立谷氨酸功能紊乱SZ小鼠模型;盐酸二甲双胍各剂量组造模同时预防性给药。对各组小鼠进行高架十字迷宫、旷场和Morris水迷宫等行为学实验。处死小鼠后,采用RT-qPCR技术检测脑组织AMPK、GRIN1、HDAC1和DGCR8等mRNA表达。结果在所有行为学检测中,空白对照组与阴性对照组差异具有统计学意义(P<0.05),表明实验动物模型构建成功。在高架十字迷宫和旷场实验中,盐酸二甲双胍高剂量组与阴性对照组差异均具有统计学意义(P<0.01),表明高剂量盐酸二甲双胍对MK-801诱导所致SZ的焦虑症状有明显缓解作用。同时,RT-qPCR结果表明高剂量二甲双胍可显著提升AMPK和GRIN1的mRNA表达(P<0.001),从而逆转阴性对照组中上述基因表达降低的趋势。结论高剂量盐酸二甲双胍对于SZ模型小鼠异常行为具有缓解作用,并可能通过AMPK和GRIN1相关信号途径发挥作用。这为临床治疗SZ提供了新的思路和线索。
Objective To explore the effects of different doses of metformin hydrochloride on behavior and candidate gene expression in mouse model of schizophrenia so as to provide new ideas and clues for clinical treatment of schizophrenia.Methods First,50 C57BL/6J mice of the same batch were randomly divided into five groups as blank control group,negative control group,and three metformin hydrochloride experimental groups(low dose 200 mg/kg,medium dose 400 mg/kg,and high dose 800 mg/kg),with 10 mice in each group.In addition,except the blank control group,all the other groups were injected intraperitoneally with dizocepin maleate(MK-801),N-methyl-D-aspartate glutamate(NMDA)receptor non-competitive antagonist.Meanwhile,metformin hydrochloride was given prophylactically at the same time in the three metformin hydrochloride experimental groups.Then,the five groups of mice were subjected to ethology experiments such as elevated plus maze,open field test,and Morris water maze.Finally,the mice's brain tissues were extracted as soon as they were killed for detection of the expressionsof AMPK,GRIN1,HDAC1 and DGCR8 at the mRNA level by RT-qPCR.Results In all the ethologic experiments,significant differences were found between the blank control group and the negative control group(P<0.05),which suggested that the experimental animal model had been successfully constructed.In the elevated plus maze test and open field test,there was a major disparity between the high-dose metformin hydrochloride experimental group and the negative control group(P<0.01),which indicated that high-dose metformin hydrochloride had a great alleviating effect on anxiety symptoms of schizophrenia induced by MK-801.At the same time,RT-qPCR results showed that high-dose metformin could proportionally increase the expression levels of AMPK and GRIN1(P<0.001),thus reversing the trend of decreased expressions of these genes in the negative control group.Conclusion High-dose metformin hydrochloride can alleviate abnormal behavior in schizophrenic model mice,and
作者
卢梦楠
陈黄韬
陶志炜
魏欣怡
赵董步甲
武姗姗
马捷
LU Mengnan;CHEN Huangtao;TAO Zhiwei;WEI Xinyi;ZHAO Dongbujia;WU Shanshan;MA Jie(Key Laboratory of Environment and Genes Related to Diseases,Xi'an Jiaotong University/Ministry of Education, Xi'an 710061, China)
出处
《西安交通大学学报（医学版）》
CAS
CSCD
北大核心
2020年第3期369-375,共7页
Journal of Xi’an Jiaotong University（Medical Sciences）
基金
国家自然科学基金资助项目(No.31371298)
国家级大学生创新性实验项目(GJ201810698126)
陕西省高等教育学会科学研究“十三五”规划课题(XGH1618)
中华医学会医学教育分会和中国高等教育学会医学教育专业委员会2018年医学教育研究立项课题(2018B-N02199)。
