The dual-functional memantine nitrate MN-08 alleviates cerebral vasospasm and brain injury in experimental subarachnoid haemorrhage models
The dual-functional memantine nitrate MN-08 alleviates cerebral vasospasm and brain injury in experimental subarachnoid haemorrhage models
复制标题
双功能硝酸美金刚MN-08减轻实验性蛛网膜下腔出血模型脑血管痉挛和脑损伤
DOI：
10.1111/bph.14763
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发表时间：
2019-07-31
影响因子：
7.3
通讯作者：
Zhang, Zaijun
中科院分区：
文献类型：
--
作者：
Luo, Fangcheng;Wu, Liangmiao;Zhang, Zaijun
背景和目的蛛网膜下腔出血（SAH）后脑血管痉挛和神经元凋亡是SAH患者发病和死亡的主要原因。到目前为止，单靶点药物还没有阻止其发生。美金刚是一种非竞争性 NMDA 受体拮抗剂，已知可以减轻 SAH 实验模型中的脑损伤和血管痉挛。 NO 可用性受损也会导致血管痉挛。最近，我们设计并合成了硝酸美金刚MN-08，它具有强大的双重功能：神经保护和血管舒张。在这里，我们测试了 MN-08 在 SAH 动物模型中的治疗效果。实验方法 体外评估了 MN-08 与 NMDA 受体（在 HEK293 细胞中表达）的结合、NO 释放和血管舒张作用。使用大鼠和兔 SAH 模型研究了 MN-08 的体内治疗效果。主要结果 MN-08 与 NMDA 受体结合，在体外和体内缓慢释放 NO。因此，MN-08 在体外放松了预先收缩的大脑中动脉，并增加了小鼠大脑皮层小血管的血流速度。然而，它并没有降低全身血压。在 SAH 血管内穿孔大鼠模型中，MN-08 改善了神经系统评分并改善了脑血管痉挛。此外，MN-08 还可以减轻兔子小脑延髓池单次注射模型中的脑血管痉挛。 MN-08 减轻大鼠和兔 SAH 模型中的神经细胞凋亡。重要的是，MN-08 的治疗效果大于美金刚。结论和意义 MN-08 具有神经保护潜力，可以改善实验性 SAH 模型中的血管痉挛。
Background and Purpose Cerebral vasospasm and neuronal apoptosis after subarachnoid haemorrhage (SAH) is the major cause of morbidity and mortality in SAH patients. So far, single-target agents have not prevented its occurrence. Memantine, a non-competitive NMDA re3ceptor antagonist, is known to alleviate brain injury and vasospasm in experimental models of SAH. Impairment of NO availability also contributes to vasospasm. Recently, we designed and synthesized a memantine nitrate MN-08, which has potent dual functions: neuroprotection and vasodilation. Here, we have tested the therapeutic effects of MN-08 in animal models of SAH. Experimental Approach Binding to NMDA receptors (expressed in HEK293 cells), NO release and vasodilator effects of MN-08 were assessed in vitro. Therapeutic effects of MN-08 were investigated in vivo, using rat and rabbit SAH models. Key Results MN-08 bound to the NMDA receptor, slowly releasing NO in vitro and in vivo. Consequently, MN-08 relaxed the pre-contracted middle cerebral artery ex vivo and increased blood flow velocity in small vessels of the mouse cerebral cortex. It did not, however, lower systemic blood pressure. In an endovascular perforation rat model of SAH, MN-08 improved the neurological scores and ameliorated cerebral vasospasm. Moreover, MN-08 also alleviated cerebral vasospasm in a cisterna magna single-injection model in rabbits. MN-08 attenuated neural cell apoptosis in both rat and rabbit models of SAH. Importantly, the therapeutic benefit of MN-08 was greater than that of memantine. Conclusion and Implications MN-08 has neuroprotective potential and can ameliorate vasospasm in experimental SAH models.