目前血管性痴呆(VD)缺乏有效治疗药物。改善患者的脑血流供应是VD治疗获得突破的关键之一。NO供体药物通过释放NO扩张血管, 有治疗VD的潜能,但大量外源性NO释放导致全身血管扩张，血压下降，脑血流反而减少。我们前期设计合成了全新的美金刚硝酸酯衍生物MN-08，体外研究发现MN-08可保护谷氨酸诱导的神经元细胞损伤，尤为重要的是首次发现MN-08可以扩张脑血管增加脑血流，而不降低外周血压；在体实验发现MN-08可以改善VD大鼠的学习认知能力和运动功能，疗效显著强于治疗痴呆药物美金刚。MN-08对VD的显著疗效是否与其具有拮抗NMDA受体和在脑内靶向释放NO扩张脑血管双重作用机理有关？本项目拟以NMDA受体拮抗和靶向NO释放为切入点，从分子、细胞和整体动物水平，进一步揭示MN-08神经保护和扩张脑血管增加脑血流的作用机理，为MN-08治疗VD提供实验基础和理论依据。

There is no effective therapeutics to the Vascular Dementia (VD). The strategic treatment on VD is to improve the cerebral blood supplying. An NO donor possesses potential treatment effect on VD by releasing free NO to dilate blood vessels, but the exogenous NO releasing may retain the risks of lessening the blood flow by dilating the general blood vessels and lowering the blood pressure. Previously, our team has designed and synthesized a brand new nitro-derivative of Memantine, MN-08, which has been proved to hold the functions of protect the neurons injury induced by glutamate in vitro. Especially, NM-08 was found to possess the functions of dilating the cerebral vessels and enhancing the blood flow, but not decreasing the peripheral blood pressure. In addition, the therapeutic efficacy of MN-08 was found to be at least 2-fold greater than that of Memantine in the vascular dementia rat model, and significantly improving the learning and motor abilities of dementia rats. The question is: if the noteworthy therapeutic effect of MN-08 is associated with its dual functions of antagonizing NMDA receptor and targeted releasing NO in the brains? Therefore, the purpose of the project is trying to clarify the exact mechanisms of MN-08 on neuroprotection, dilating the cerebral vessels and improving the cerebral blood flow based on its roles in antagonizing NMDA receptor and targeted releasing NO in the brain. The results will provide experimental and theoretical evidences for MN-08 in the treatment VD.