参归三圣散通过调控VIP/VIPRs通路减缓缺血性脑卒中延迟tPA溶栓所致血脑屏障加重损害的研究

流行病学数据显示我国是世界上背负脑卒中负担最重的国家之一，30年来缺血性脑卒中发病率和死亡率仍呈上升趋势，但常用的溶栓制剂tPA却因严格时间窗限制和破坏血脑屏障（BBB）引致高出血转化风险，导致其受益率仅为6.5%。为此，延长tPA治疗时间窗、保护卒中后BBB降低出血转化风险，是临床上一个亟待解决的难题。前期研究发现古方参归三圣散能够降低缺血性脑卒中大鼠BBB渗漏、改善神经功能，其机制与活化血管活性肠肽（VIP）通路有关。VIP信号通路对缺血性脑卒中显示出多重保护作用。为此，本研究拟将参归三圣散应用在缺血性脑卒中大鼠模型上，确定其对延长tPA治疗时间窗所致BBB加重损害的减缓作用，以及与靶向减轻神经血管单元损伤的VIP/VIPRs网络通路关联，明确其药效作用物质基础及对应的分子靶标，全新揭示中药复方综合调控路径。为达到扩大tPA治疗受益范围、降低出血转化风险的目标提供新的治疗策略。

Epidemiological data indicate China has been one of nations with the biggest stroke burden in the world, and the incidence and mortality of ischemic stroke always present high trends in the past 30 years. Due to the rigorous limitation of tissue plasminogen activator (tPA) therapeutic time window and tPA disrupting blood-brain barrier (BBB) resulting in the high risk of hemorrhagic transformation (HT), only 6.5% patients can receive tPA therapeutic benefits. Therefore, it is an urgent problem to be resolved how to extend the time window for thrombolysis of tPA and protect BBB so as to decrease the risk of HT post-stroke. Previous study suggested that Shengui Sansheng San (SSS) attenuated BBB permeability and improved neurological function via activation of vasoactive intestinal peptide (VIP) and its receptors in the rat middle cerebral artery occlusion (MCAo) model. VIP pathway plays multiple protective roles in ischemic stroke. In the study, we employ SSS for investigating the attenuated effects on the exacerbation of BBB disruption resulting from extending the time window for thrombolysis of tPA in the rat MCAo model, and discover if the mechanisms are related to VIP/VIPRs network pathways targeting the alleviation of neurovascular unit injury. Simultaneously, we also interpret the relation of SSS's main active compounds with their corresponding to molecular targets. It contributes to elucidating the comprehensive regulatory approaches of Chinese medicinal formula. Our study can provide novel therapeutic strategy for extending time window for thrombolysis of tPA and decreasing the risk of HT after ischemic stroke.