靶向调节HDAC6增加t-PA静脉溶栓治疗的有效性及安全性研究

Thrombolysis with tissue-type plasminogen activator (t-PA) is the only approved and evidence-based medical therapy for ischemic stroke. Hemorrhagic transformation (HT) is the major complication of tissue plasminogen activator (t-PA). Disruption of the Blood brain barrier（BBB） is central to HT formation in ischemic stroke. After ischemic brain injury, disruption of the BBB occurs early, and can be aggravated by t-PA. Histone deacetylase(HDAC) inhibitor can protect the integrity and permeability of the blood brain barrier through reducing the expression of Matrix metalloproteinases(MMPs) or/and inflammation. Our research have found that targeted inhibition of HDAC6 can alleviate brain edema and BBB permeability in rat ischemia model. Based on these findings, we set out this study to evaluate the effects and mechanism of HDAC6 on HT induced by focal cerebral ischemia treated with t-PA. These findings will give us a new insight into the combination therapy of thrombolysis with t-PA.

组织型纤溶酶原激活剂（tissue-type plasminogen Activator，t-PA）溶栓治疗目前是唯一经FDA认可的缺血性脑卒中的药物治疗方法，但是严格的时间窗以及溶栓相关副作用限制了它的临床使用。溶栓最主要的副作用为致死性脑出血转化，其发生与缺血后血脑屏障的破坏，通透性增高有关，且t-PA治疗会加重此损伤过程。组蛋白去乙酰化酶抑制剂（Histone Deacetylase inhibitor，HDACI）可通过抑制脑缺血后MMPs表达或减轻炎症反应，保护血脑屏障的完整性及通透性。