NMDAR介导的兴奋毒性是缺血性卒中发病的关键环节，传统的NMDAR拮抗剂副反应严重导致临床转化失败，美金刚是获准临床使用（治疗阿尔兹海默病）的NMDAR拮抗剂。在以往研究中，我们发现咪唑啉I2受体的外源性配体2-BFI能够可逆地抑制NMDAR介导的Ca2+内流，其方式与美金刚相似，抵抗谷氨酸兴奋毒性；用膜片钳技术证实2-BFI短暂、可逆、非竞争性抑制过度激活的NMDAR电流，解离速度比美金刚更快。因此，2-BFI是一种非常有希望转化到临床的新型神经保护剂候选药物。前期我们采用脑缺血建模后即刻给药的方法证实2-BFI有明确的保护作用。本项目将探讨在脑缺血建模后给药2-BFI的保护作用、有效给药时间窗、能否保护神经血管单元、与rt-PA的联合效应等临床前关键问题, 采用OGD细胞模型，从抑制[Ca2+]超载及相关级联反应角度揭示2-BFI保护脑缺血的机制，为2-BFI的临床转化奠定理论基础。

Excitotoxicity mediated by NMDAR is the key step for the pathogenesis of ischemic stroke. The traditional NMDAR antagonists transformed fail for the serious side effects. Memantine is allowed to clinical use (treatment of Alzheimer's disease) of NMDAR antagonists. In previous studies, We found that exogenous ligand of imidazoline I2 receptor 2-BFI reversibly blocks NMDAR-mediated [Ca2+]i influx in a manner similar to that of memantine providing neuroprotection against glutamate toxicity，We confirmed that 2-BFI transiently 、reversibly、 noncompetitively inhibits NMDAR with a faster dissociation than those of memantine using the patch clamp technique. Therefore, 2-BFI is a new neuroprotective drug candidate that is very promising for transformation to clinical. .Early, We found 2-BFI have obvious protective effect on ischemic brain injury by immediate administration 2-BFI after establish the model of cerebral ischemia. In this project we will use animal experiment to investigate whether 2-BFI have protective effect for ischemic stroke by administration after establish the model of cerebral ischemia, the effective treatment time window, whether 2-BFI have comprehensive protection for the neurovascular unit, and the effect of 2-BFI combine with rt-PA ; using OGD cell model in vitro, we will investigate the mechanism of 2-BFI protecting cerebral ischemic injury from inhibiting [Ca2+] overload and related cascade , these will lay the theoretical foundation for 2-BFI transformation to clinical.