药学学报, 2019, 54(3): 448-453
引用本文:
陈燕霞, 孔令雷, 王海港, 石瑞丽, 杜冠华. 匹诺塞林在t-PA溶栓所致出血转化中的作用[J]. 药学学报, 2019, 54(3): 448-453.
CHEN Yan-xia, KONG Ling-lei, WANG Hai-gang, SHI Rui-li, DU Guan-hua. The role of pinocembrin in t-PA thrombolysis-induced hemorrhagic transformation[J]. Acta Pharmaceutica Sinica, 2019, 54(3): 448-453.

匹诺塞林在t-PA溶栓所致出血转化中的作用
陈燕霞1,3, 孔令雷2, 王海港2, 石瑞丽1,3, 杜冠华2
1. 包头医学院生理学教研室, 内蒙古 包头 014040;
2. 中国医学科学院、北京协和医学院药物研究所, 北京市药物靶标研究与药物筛选重点实验室, 北京 100050;
3. 包头医学院神经科学研究所, 内蒙古 包头 014040
摘要:
出血转化(hemorrhagic transformation,HT)是缺血性脑卒中的常见严重并发症,尤其是在溶栓治疗后,显著增加卒中的致残率及死亡率。组织纤溶酶原激活剂(tissue plasminogen activator,t-PA)是被美国FDA批准的唯一用于脑卒中的溶栓药物,由于治疗时间窗窄和易引发出血转化,限制了其临床应用。目前HT的病理机制和治疗靶点尚不清楚,临床无有效防治药物。匹诺塞林是一种天然黄酮类化合物,对脑卒中具有显著的治疗作用,目前已经作为I类抗脑缺血新药进入Ⅱ期临床试验。匹诺塞林对脑卒中后HT的发生尚未有研究,因此,本研究考察了匹诺塞林对t-PA溶栓治疗所致出血转化的作用。大鼠缺血6 h后,尾静脉静滴t-PA诱导出血,匹诺塞林(5、10和20 mg·kg-1)于t-PA前5 min尾静脉注射,缺血24 h后检测梗死体积、神经功能及血红蛋白含量,Evans blue渗漏实验评价血脑屏障(blood-brain barrier,BBB)完整性。动物实验遵循北京协和医学院动物伦理委员会规定。结果显示,缺血6 h后给予t-PA显著加重脑损伤,梗死体积和脑含水量分别达到39%和83.4%,促进HT的发生。预先给予匹诺塞林能够使梗死体积和脑含水量分别降至28.5%和80.3%,改善神经功能。此外,联合应用匹诺塞林能使脑组织血红蛋白含量及Evans blue含量分别降低50%和40%,表明匹诺塞林可以保护BBB完整性且降低HT的发生。其中,10 mg·kg-1剂量最佳。这些结果表明,匹诺塞林和t-PA联用能对抗脑缺血,抑制HT的发生。因此,匹诺塞林可能是治疗t-PA溶栓所致HT的潜在药物。
关键词:    出血转化      组织纤溶酶原激活剂      匹诺塞林      血脑屏障      缺血性脑卒中     
The role of pinocembrin in t-PA thrombolysis-induced hemorrhagic transformation
CHEN Yan-xia1,3, KONG Ling-lei2, WANG Hai-gang2, SHI Rui-li1,3, DU Guan-hua2
1. Department of Physiology, Baotou Medical College, Baotou 014040, China;
2. Beijing Key Laboratory of Drug Targets Identification and Drug Screening, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China;
3. Institute of Neuroscience, Baotou Medical College, Baotou 014040, China
Abstract:
Hemorrhagic transformation (HT) is a frequent complication of ischemic stroke, especially after thrombolytic therapy. This event is associated with increased morbidity and mortality. Tissue plasminogen activator (t-PA), the only FDA proved drug for breaking blood clots, is underutilized in ischemic stroke, because of its limited therapeutic window and hemorrhagic complications. Due to the lack of clear understanding of the pathological mechanism, there are no effective drugs to decrease the incidence of HT. Pinocembrin is a natural flavonoid compound and has neuroprotective effects in animal ischemic stroke models. In this study, we investigated the role of pinocembrin in t-PA thrombolysis-induced HT in rat thromboembolic stroke model. t-PA was administrated 6 h after ischemia and pinocembrin (5, 10 and 20 mg·kg-1) was given 5 min before t-PA administration. Infarct volume, neurological score and hemoglobin content were evaluated at 24 h after ischemia. Evans blue leakage was used to detect blood-brain barrier (BBB) permeability. All procedures were approved by the Institutional Animal Care and Use Committee of the Peking Union Medical College. The results showed that treatment with t-PA at 6 h after ischemia aggravated brain injury and increased the risk of HT, with infarct volume and brain water content reached 39% and 83.4%, respectively. Pretreatment with pinocembrin decreased the infarct volume and brain water content to 28.5% and 80.3%, and improved neurological function. In addition, the combined application of pinocembrin with t-PA reduced hemoglobin content and Evans blue content in brain tissue by 50% and 40%, indicating that pinocembrin could protect the BBB permeability and reduce the occurrence of HT. Among these doses, 10 mg·kg-1 is most effective. In conclusion, our results demonstrate that the combination of pinocembrin with t-PA protects against cerebral ischemia, reduces the occurrence of HT induced by t-PA thrombolysis. Thus, pinocembrin may be a potential therapeutic drug for t-PA induced HT.
Key words:    hemorrhagic transformation    tissue plasminogen activator    pinocembrin    blood-brain barrier    ischemic stroke   
收稿日期: 2018-11-23
DOI: 10.16438/j.0513-4870.2018-1062
基金项目: 国家重点研发计划(2016YFC1000905);"重大新药创制"科技重大专项(2018ZX09711001-009-009);中国医学科学院医学与健康科技创新工程(2016-I2M-3-007);北京市自然科学基金面上项目(7182113);内蒙古自然科学基金项目(2017MS0808);内蒙古自治区高等学校科学研究项目(NJZC17244);包头医学院博士基金项目(BSJJ201625).
通讯作者: 石瑞丽, 杜冠华
Email: ruilishi@sina.com;dugh@imm.ac.cn
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