HMGB1/TLRs在异氟烷对aSAH后迟发性脑缺血神经保护作用的机制研究

The delayed cerebral ischemia (DCI) is the main cause of neural damage after aneurysmal subarachnoid hemorrhage (aSAH). Recent findings show that iso?urane postconditioning (IPC) may attenuate the inflammation after aSAH, and play the neuroprotective role in the pathogenesis of DCI, However, mechanism is unclear. Our previous studies have found that IPC inhibit the expression of HMGB1 in the cerebrospinal fluid and brain tissue of aSAH model. Accordingly, we hypothesized that IPC may play a neuroprotective role in the pathogenesis of DCI in aSAH via HMGB1 and its receptor (RAGE, TLR2 / 4) pathway. In this project, by establishing SAH animal model and using morphological, molecular biology, CT brain perfusion imaging and behavioral techniques, we aim to explore the following problems, including (1) the effect of IPC in the expression of HMGB1 and its receptor in the central nervous system of aSAH model ; (2) the effect of IPC in cerebral perfusion, neuronal apoptosis and animal behavior of aSAH model. Through research, we will initially clarify the neuroprotective mechanism of isoflurane by HMGB1 receptor pathway in the pathogenesis and progression of DCI after aSAH, and will provide a new strategy for the clinical treatment of DCI after aSAH.

迟发性脑缺血(DCI)是动脉瘤蛛网膜下腔出血（aSAH）神经损伤的主要原因。最新研究显示，异氟烷后处理（IPC）通过干预aSAH后炎症反应在DCI的病理过程中发挥神经保护作用，但其机制尚不清楚。我们前期研究发现，IPC可抑制aSAH模型脑脊液和脑组织中HMGB1的表达。据此，我们推测IPC可能通过HMGB1及其受体（RAGE、TLR2/4）通路在aSAH后DCI的病理过程中发挥神经保护作用。在本项目中，我们以SAH动物模型为研究对象，采用形态学、分子生物学、CT脑灌注成像、行为学等技术，探讨:（1）IPC对aSAH模型中枢神经系统HMGB1及其受体时空表达的影响；（2）IPC通过HMGB1通路对aSAH后脑血流灌注、神经元凋亡以及动物行为的影响。通过研究，将初步阐明异氟烷通过HMGB1及受体通路在aSAH后DCI病理进展中的神经保护机制，为aSAH后DCI的临床治疗提供新策略。