摘要
目的探索新型胰高血糖素样肽-1/葡萄糖依赖性促胰岛素样肽(GLP-1/GIP)双受体激动剂DA3-CH对匹罗卡品诱导的大鼠癫痫持续状态(SE)后海马神经元凋亡的影响,进而探讨其神经保护作用.方法将108只体质量为250~300g的健康成年雄性SD大鼠随机分为正常对照组(NS组,n=12)、癫痫持续状态模型组(SE组,n=48)、DA3-CH干预组(SE+DA3组,n=48),SE组和SE+DA3组分别据造模成功后观察指标的不同时间点(SE后12h、1d、3d、7d)分为4个亚组(每个亚组n=12).腹腔注射匹罗卡品(30mg·kg^-1诱导SE模型,造模成功后,SE+DA3组大鼠每日进食前给予腹腔注射DA3-CH(101nmoL·kg^-1,NS组及SE组大鼠给予等体积生理盐水.各亚组分别于SE后12h、1d、3d、7d检测空腹尾静脉血糖水平后处死取脑,采用免疫组化和Western blot方法检测海马中凋亡相关蛋白Bax、Bcl-2及神经元核抗原NeuN的表达水平.结果①NS组、SE组、SE+DA3组各亚组大鼠之间的空腹尾静脉血糖水平差异无统计学意义(P>0.05);②免疫组化与Western blot结果显示,NS组、SE组、SE+DA3组各亚组大鼠之间海马Bax、Bcl-2、NeuN表达水平差异均有统计学意义(P<0.001);与NS组相比,SE组大鼠海马Bax、Bcl-2表达水平升高,NeuN表达水平降低;与SE组相比,SE+DA3组大鼠海马Bax表达水平降低,Bcl-2、NeuN表达水平升高.结论新型GLP-1/GIP双受体激动剂DA3-CH可抑制大鼠癫痫持续状态导致的海马神经元凋亡,减少神经元丢失,具有神经保护作用.
Objective To explore the effect of novel dual-GLP- 1/GIP receptor agonist DA3-CH on the apoptosis of hippocampal neurons in the rat after status epilepticus ( SE ) induced by pilocaipine, and to investigate its neuroprotective effect. Method A total of 108 healthy adult male Sprague-Dawley ( SD ) rats weighing 250-300g were randomly divided into a normal control group ( NS group, n=12 ), a SE model group ( SE group, n=48 ), and a DA3- CH-treated group ( SE+DA3 group, n=48 ). SE group and SE+DA3 group respectively composes of 4 subgroups ( n=12 per subgroup ), with each subgroup corresponding to the different time period after the onset of SE: 12h, Id, 3d, 7d. Pilocarpine ( 30mg ? kg^-1 )was administered intraperitoneally (ip.) to induce SE model. After successfully induced, the rats of SE+DA3 group were injected DA3-CH ( lOnmoL?kg^-1, ip.) once-daily before the animals' meals, while the rats of NS group and SE group were received the same volume of nonnal saline instead of DA3-CH. The rats of each subgroup were detected the fasting glucose levels of tail ￥&n and then sacrificed to take out the brain tissue at 12h, Id, 3d, 7d after SE. Expression of Bax and Bcl-2 ( apoptosis-related proteins ) and NeuN ( neuronal nuclei) in hippocampus were detected by immunohistochemistry and Western blot analysis. Results ① There is no statistical significance in the fasting glucose levels of tail vein between subgroups of NS group, SE group and SE+DA3 group (P>0.05 );② The results of immunohistochemistry and Western blot analysis show that the difference in hippocampal expression of Bax, Bel-2 and NeuN is statistically significant between subgroups of NS group, SE group and SE+DA3 group (P<0.001);Compared with NS group, SE group show increased expression of Bax and Bcl-2 and decreased expression of NeuN in hippocampus;Treatment with DA3-CH show decreased expression of Bax and increased expression of Bcl-2 and NeuN in hippocampus compared with SE group. Conclusion Novel dual-GLP-1 /GIP receptor agonists DA3-CH has neuropro
作者
田森晶
薛国芳
Christian H?lscher
张晓敏
孟鹏飞
袁振宇
Tian Miaojing;Xue Guofang;Christian Holscher;Zhang Xiaomin;Meng Pengfei;Yuan Zhenyu(Department of Neurology, the Second Affiliated Hospital cf Shanxi Medical University, Taiyuan 030000, China)
出处
《脑与神经疾病杂志》
2019年第7期397-405,共9页
Journal of Brain and Nervous Diseases
基金
国家自然科学基金(81601038)
中国抗癫痫协会癫痫科研基金-UCB基金(2017007)
山西省科技厅青年科技研究基金(2014021038-4)
山西医科大学校科技创新基金(057602)
