The dual‐functional memantine nitrate MN‐08 alleviates cerebral vasospasm and brain injury in experimental subarachnoid haemorrhage models
| Autor: | Yuqiang Wang, Yifan Han, Zhixiang Zhang, Zheng Liu, Gaoxiao Zhang, Yewei Sun, Xifei Yang, Shupeng Li, Shinghung Mak, Jun Ju, Fangcheng Luo, Zaijun Zhang, Ning Li, Baojian Guo, Liangmiao Wu, Zeyu Zhu, Qiang Zhou |
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| Rok vydání: | 2019 |
| Předmět: |
Male
0301 basic medicine Vasodilator Agents Perforation (oil well) Pharmacology Nitric Oxide Cisterna magna Neuroprotection Rats Sprague-Dawley Mice Structure-Activity Relationship 03 medical and health sciences 0302 clinical medicine Cerebral vasospasm Memantine medicine.artery medicine Animals Humans Vasospasm Intracranial cardiovascular diseases Nimodipine Nitrates Dose-Response Relationship Drug business.industry Vasospasm Subarachnoid Hemorrhage medicine.disease Research Papers Rats nervous system diseases Mice Inbred C57BL Disease Models Animal HEK293 Cells 030104 developmental biology Brain Injuries Middle cerebral artery Rabbits business 030217 neurology & neurosurgery medicine.drug |
| Zdroj: | Br J Pharmacol |
| ISSN: | 1476-5381 0007-1188 |
| DOI: | 10.1111/bph.14763 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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