银杏二萜内酯葡胺注射液的脑血管保护作用研究

李卓琼+曹泽彧+曹亮+柯志鹏+王振中+萧伟

[摘要] 采用颈内动脉插入尼龙线栓来制作大鼠左侧大脑中动脉栓塞（middle cerebral artery occlusion，MCAO）模型，检测给药14 d后的各组大鼠行为学评分、脑梗死面积、脑含水量、EB溢出量、凝血四项及脑组织occludin，MMP-9表达的差异，研究在前期实验中对脑缺血性损伤具有明显保护作用的银杏二萜内酯葡胺注射液的保护作用是否与降低血脑屏障通透性、降低出血风险有关，并探讨其可能的作用机制。实验发现银杏二萜内酯葡胺注射液在24 h能有效缓解MCAO引起的行为学病变，降低行为学评分，改善脑组织水肿，减少EB溢出率，降低长期给药可能造成的出血倾向，明显减少模型大鼠缺血侧脑组织occludin的缺失，下调MMP-9的表达。以上结果表明银杏二萜内酯葡胺注射液对抗脑缺血有明显效果，其治疗作用的发挥可能主要依赖于降低血脑屏障通透性从而改善脑水肿。

[关键词] 银杏二萜内酯葡胺注射液； 脑缺血； 血管保护

[Abstract] The left middle cerebral artery occlusion （MCAO） model was made by inserting the nylon thread plug into the internal carotid artery. The behavioral score， cerebral infarction area， brain water content， ethidium bromide （EB） spillover， coagulation four indices， occludin and MMP-9 expression in brain tissues were detected after 14 days of administration， to investigate whether the protective effect of ginkgo diterpene lactone meglumine injection （GDLMI） which had obvious protective effect on cerebral ischemic injury in the previous experiment was related to reducing the permeability of the blood-brain barrier （BBB） and reducing the risk of bleeding， and to explore its possible mechanism of action. The results showed that GDLMI could effectively alleviate the behavioral changes caused by MCAO at 24 h， reduce the behavioral score， improve the edema of brain tissue， reduce the EB overflow rate， reduce the bleeding tendency caused by long-term administration， significantly reduce the occlusion deficiency in ischemic brain tissue of model rats， and down-regulate MMP-9 expression. The above results indicate that GDLMI has obvious effect on cerebral ischemia， and the therapeutic effect of GDLMI may mainly depend on lowering the permeability of blood-brain barrier to improve brain edema.

[Key words] ginkgo diterpene lactone meglumine injection； cerebral ischemia； vascular protection

銀杏二萜内酯葡胺注射液（ginkgo diterpene lactone meglumine injection，GDLMI）是江苏康缘药业股份有限公司研发的治疗缺血性脑卒中的五类新药，主要由银杏二萜内酯A（ginkgolide A）、银杏二萜内酯B（ginkgolide B） 和银杏二萜内酯K（ginkgolide K）组成，具有活血通络之功效，临床用于中风病中经络痰瘀阻络证（脑梗死）的治疗，症见半身不遂、口舌歪斜、言语謇涩、肢体麻木等。脑梗死后，脑组织MMP家族被激活，它们降解了血脑屏障（BBB）血管基底膜和细胞外基质上边的TJs，使血脑屏障被破坏，通透性增高，诱发脑水肿甚至出血损伤。本文采用颈内动脉插入尼龙线栓来制作大鼠左侧大脑中动脉栓塞（middle cerebral artery occlusion，MCAO）模型，检测给药14 d后的各组大鼠行为学评分、脑梗死面积、脑含水量、EB溢出量、凝血四项及脑组织occludin，MMP-9表达的差异，研究在前期实验中对脑缺血性损伤具有明显保护作用[1-2]的GDLMI的药效是否与降低BBB通透性有关，并探讨其可能的作用机制。

1 材料

1.1 试剂

银杏二萜内酯葡胺注射液（GDLMI）由江苏康缘药业股份有限公司提供，规格5 g·L-1，5 mL/支，批号130902。

尼莫地平片（拜耳医药保健公司·中国北京，批号122296）；银杏叶提取物注射液（EGb，规格5 mL：17.5 mg，台湾济生化学制药厂股份有限公司，批号10041）；拜阿司匹林肠溶片（拜耳医药保健有限公司，批号BJ26992）；波立维硫酸氢氯吡格雷片[赛诺菲（杭州）制药有限公司，批号5A421]。endprint