链脲佐菌素诱导2型糖尿病大鼠合并脑缺血再灌注损伤模型优化方法的研究

中国临床药理学与治疗学 ›› 2017, Vol. 22 ›› Issue (5): 518-525.

链脲佐菌素诱导2型糖尿病大鼠合并脑缺血再灌注损伤模型优化方法的研究

刘畅^1,2，姜道利³，刘小芳¹，徐佳¹，王瓅珏²，王茜²，许羚⁴，方翼²

¹徐州医科大学研究生院，徐州 221004，江苏；²北京大学人民医院药剂科，北京 100044；³徐州医科大学附属医院药剂科，徐州 221006，江苏；⁴上海中医药大学药物临床研究中心，上海 201203

收稿日期:2017-01-06 修回日期:2017-03-08 出版日期:2017-05-26 发布日期:2017-05-27
通讯作者: 方翼，男，博士，主任药师，教授，硕士生导师，研究方向：临床合理用药与新药临床试验。 Tel：010-66583834 E-mail：fygk7000@163.com
作者简介:刘畅，女，硕士研究生，研究方向：临床合理用药与新药临床试验。 Tel：15951713567 E-mail：15951713567@163.com
基金资助:
北京大学人民医院研究与发展基金（RDB2013-22）

Establishment of rat model of type 2 diabetes induced by streptozotocin combined with cerebral ischemic reperfusion injury

LIU Chang ^1,2, JIANG Daoli ³, LIU Xiaofang ¹, XU Jia ¹, WANG Lijue ², WANG Qian², XU Ling ⁴, FANG Yi²

¹Post-graduate Department, Xuzhou Medical University, Xuzhou 221004, Jiangsu, China; ²Pharmacy Department, Peking University People's Hospital, Beijing 100044, China; ³ Pharmacy Department, the Affiliated Hospital of Xuzhou Medical University, Xuzhou 221006, Jiangsu, China; ⁴Clinical Drug Research Center, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China

Received:2017-01-06 Revised:2017-03-08 Online:2017-05-26 Published:2017-05-27

摘要/Abstract

摘要：

目的: 为2型糖尿病（T2DM）合并脑缺血治疗新药的机制研究，探索T2DM合并脑缺血再灌注（T2DM-MCAO/R）损伤大鼠模型建立的优化方法。方法: 以4至5周高脂高糖（HFG）饮食诱导胰岛素抵抗，注射链脲佐菌素（STZ）形成T2DM模型，按STZ注射剂量分为A、B、C、D、E五种方法。再建立T2DMMCAO/R损伤大鼠模型：A、B、C法采用颈总动脉（CCA）进线法，D、E法用颈外动脉（ECA）进线法；A法为单次给药，B、C法连续给药3 d，D、E法在手术前连续给药2周。通过观测大鼠的症状，测量各阶段体质量和空腹血糖（FBG）、手术后神经功能行为学评分等来评价成模率和模型质量。结果: T2DM-MCAO/R成模率为80.0%、77.8%、84.6%、100.0%、100.0%，其中，E法T2DM成模率最高，为93.3%，死亡率最小。胰岛素和尼莫地平都可以使模型大鼠血糖和神经功能行为学明显改善，并使脑梗死面积减小。结论: 以两次低剂量注射STZ，结合ECA进线法手术，建立T2DM-MCAO/R损伤大鼠模型，成模率高，死亡率低，稳定性好，是成功的优化模型，值得推广应用于T2DM合并脑缺血治疗新药的作用与机制研究。

关键词: 2型糖尿病, 链脲佐菌素, 再灌注损伤

Abstract:

AIM: To investigate an optimized rat model establishment of type 2 diabetes mellitus (T2DM) induced by streptozotocin (STZ) combined with cerebral ischemic reperfusion injury (T2DM-MCAO/R) so as to help the study of new drug for acute cerebral ischemia/reperfusion injury subjected to type 2 diabetes mellitus (T2DM). METHODS: High-fat and high-sugar (HFG) diet for 4 or 5 weeks were administered to induce insulin resistance, and STZ of different doses were injected to induce T2DM model. Models of T2DM-MCAO/R were built through five methods (A, B, C, D, E) with different doses of streptozotocin (STZ). Method A, B and C developed T2DM-MCAO/R injury models by surgery with sutures into brain from CCA; Method D and E, sutures from ECA. Method A administered drugs along with reperfusion; Method B and C injected drugs every day from reperfusion to 72 h; Method D and E, drugs were injected every day for two weeks before surgery. Syndrome, weight and fasting blood glucose (FBG) were assessed in various stages, and neurological behavioral scores were measured after the surgery to assess the quantity and quality of successful models. RESULTS: With method A-E, 80%, 77.8%, 84.6%, 100%, 100% rats were successfully modeled. While 93.3% rats were successfully induced T2DM model by method E with the highest success rate and lowest death rate. Nimodipine and insulin could all improve the fasting blood glucose level, neurological deficits and reduced infarction volume percentage at the same time. CONCLUSION: Rat model of T2DM-MCAO/R injury established by two times injection of low dose STZ and MCAO/R surgery (introduced from ECA) present higher successful modeling rate, lower death rate and better stability. It is referential to investigate the effect and mechanism of new medicine for preventing and treating ischemia/reperfusion injury subjected to T2DM.

Key words: type 2 diabetes mellitus, streptozotocin, reperfusion injury

中图分类号:

R965.2

刘畅，姜道利，刘小芳，徐佳，王瓅珏，王茜，许羚，方翼. 链脲佐菌素诱导2型糖尿病大鼠合并脑缺血再灌注损伤模型优化方法的研究[J]. 中国临床药理学与治疗学, 2017, 22(5): 518-525.

LIU Chang, JIANG Daoli, LIU Xiaofang, XU Jia, WANG Lijue, WANG Qian, XU Ling, FANG Yi. Establishment of rat model of type 2 diabetes induced by streptozotocin combined with cerebral ischemic reperfusion injury[J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2017, 22(5): 518-525.

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