血脑屏障破坏对急性高血压脑水肿形成作用的磁共振动态量化研究

Hypertensive encephalopathy (HTE) is a potentially fatal condition associated with blood-brain barrier (BBB) disruption and cerebral edema development. The pathogenesis leading to this condition has not been well addressed and the molecular pathways are unknown either. On the basis of our experimental research on HTE and clinical studies on posterior reversible encephalopathy syndrome (PRES), we put forward the hypothesis of δPKC activation may be a pivotal signaling event which dysregulates structural and functional integrity of tight junctions and BBB disruption leading to brain edema and encephalopathy onset. We determine the role of δPKC on HTE model by infusing subcutaneously δV1-1 selective peptide inhibitor of δPKC.The mortality rate, behavioral symptom, blood pressure and BBB permeability, microvasculature disruption are compared between acute, chronic hypertensive groups and control group.Cerebral blood flow is tested with laser doppler flowmetry,brain edema is obserbed using micro-MRI multimodal imaging,as well as BBB permeability with real-time florescence imaging. To investigate the role of δPKC playing in tight junction disruption, BBB breakdown and brain edema development. we would elucidate the molecular mechanism involved in HTE and a potentially therapeutic target for prevention of BBB disruption or reduction of cerebrovascular injury would be tested in hypertension-induced encephalopathy in rats. If a similar mechanism occurs in humans, a δPKC inhibitor may be useful for patients at risk of hypertension-induced encephalopathy and stroke.

高血压脑病(HTE)是一种可致患者认知障碍和机体残疾的神经系统急症，常合并血脑屏障(BBB)破坏、脑水肿及脑出血。在对HTE、可逆性后部脑病综合征(PRES)前期研究的基础上，我们提出高血压导致毛细血管滤过压增加和内皮细胞功能障碍(ECD)导致BBB破坏是脑水肿形成主要因素的假设，采用micro-MRI动态观察急性高血压大鼠脑水肿分布、动态变化，定量计算脑血流灌注参数及BBB通透性，利用激光多谱勒血流仪动态测定脑血流量(CBF)及血压，实时荧光成像观察BBB通透性，伊文氏蓝判断BBB破坏情况；在不同时间点皮下注射PKCδ抑制剂--V1-1δ，探索PKCδ激活通路在急性高血压导致的ECD、BBB破坏及脑水肿形成中的作用。本研究基于动态定量MRI平台研究BBB破坏及ECD将有助于揭示HTE发病的分子机制，可望成为研究HTE发病机制的重要突破口，为临床治疗提供新靶点，开辟临床治疗的新途径。

高血压脑病(HTE)是一种可致患者认知障碍和机体残疾的神经系统急症，常合并血脑屏障(BBB)破坏、脑水肿及脑出血。但相关的发病机制尚不清楚。对HTE发病机制的研究和认识不但有利于探讨其病理生理学改变，更有利于其诊断、治疗及预后评价，对降低患者的致残率和死亡率有重要意义。我们根据提出的蛋白激酶Cδ(PKCδ)的激活可能是破坏细胞间紧密连接(TJ)和BBB结构、功能完整性并导致 HTE 的关键信号通路的假设，在不同时间点对高血压大鼠模型皮下注射PKCδ抑制剂——V1-1δ，观察V1-1δ对高血压大鼠死亡率、脑病症状、血压、TJ及BBB通透性的影响， 并对不同高血压模型及BBB直接破坏模型，利用激光多谱勒血流仪（LDF）测定CBF及血压， 多模态micro-MRI动态观察脑水肿的变化、BBB通透性改变及静息态脑网络， 伊文氏蓝判断BBB破坏范围，Western blot和免疫染色进行BBB相关蛋白测定。探索PKCδ激活通路在导致HTE内皮细胞功能障碍、BBB破坏及脑水肿形成中的作用，对进一步阐明HTE的发病机制具有重要意义，为HTE治疗靶点的选择提供依据。