创新药物MN-08改善毛细血管痉挛和微循环障碍治疗蛛网膜下腔出血的机制研究

毛细血管痉挛和微循环障碍是蛛网膜下腔出血（SAH）后早期脑损伤的主要原因，但对此缺乏有效防治措施。毛细血管缺少平滑肌层，周细胞包绕毛细血管外径，是调控毛细血管收缩和脑微循环的核心细胞。SAH后溶血产物和过度激活的NMDA受体，介导周细胞紧缩或死亡，引起毛细血管痉挛及微循环障碍。我们前期研究发现：新型美金刚硝酸酯MN-08具有拮抗NMDA受体抑制细胞损伤，靶向NMDA受体释放NO扩张脑血管的双重作用，可减轻SAH大鼠和新西兰兔血管痉挛。据此，我们推测MN-08拮抗NMDA受体释放NO，通过保护和调节毛细血管周细胞功能，改善毛细血管痉挛及微循环障碍，从而减轻SAH早期脑损伤。本项目拟采用原代周细胞、离体脑片、周细胞缺陷(Pdgfrβ+/−)小鼠作为研究对象，结合分子生物学、特异性抑制剂、双光子显微镜等技术手段，阐明MN-08改善毛细血管痉挛及微循环障碍的分子机制，为SAH临床治疗提供新策略。

Capillary spasm and microcirculation dysfunction are the main causes of early brain injury after subarachnoid hemorrhage (SAH). However, there is no effective treatment for SAH. Cerebral capillary lack a continuous smooth muscle layer. Pericytes surrounded capillary outer diameter, which are the dominant cells in regulating the contraction of capillary and cerebral microcirculation. After SAH, hemolysate and over-activated NMDA receptor mediate the shrinkage or death of pericytes, causing capillary spasm and microcirculation dysfunction. Our previous studies indicated that memantine nitrate MN-08 has the dual effects of antagonizing N-methyl-D-aspartate (NMDA) receptors and releasing nitric oxide (NO) to dilate cerebral blood vessels. Moreover, MN-08 alleviates cerebral vasospasm in experimental rat and rabbit SAH models. Accordingly, we hypothesize that MN-08 protects and regulates the pericytes function by binding NMDA receptors to releases NO in the brain, which attenuates capillary spasm and microcirculation disturbance, thereby reducing early brain injury after SAH. In this proposal, we will use the primary pericytes, isolated brain slices and pericyte-deficient (Pdgfrβ+/−) mice, and combine the techniques such as molecular biology, specific inhibitors and two-photon imaging to elucidate the molecular mechanism of MN-08 in ameliorating cerebral capillary spasm and microcirculation dysfunction after SAH. The accomplishment of this project will provide a novel strategy for the clinical treatment of SAH.