Fangcheng Luo1, Liangmiao Wu1, Zhixiang Zhang1, Zeyu Zhu1, Zheng Liu1, Baojian Guo1, Ning Li1, Jun Ju2, Qiang Zhou2, Shupeng Li2, Xifei Yang3, Shinghung Mak4,5, Yifan Han4,5, Yewei Sun1, Yuqiang Wang1, Gaoxiao Zhang1, Zaijun Zhang1,6. 1. Institute of New Drug Research and Guangzhou Key Laboratory of Innovative Chemical Drug Research in Cardio-cerebrovascular Diseases, Jinan University College of Pharmacy, Guangzhou, China. 2. School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Shenzhen, China. 3. Key Laboratory of Modern Toxicology of Shenzhen, Center for Disease Control and Prevention, Shenzhen, China. 4. State Key Laboratory of Chinese Medicine and Molecular Pharmacology (Incubation), The Hong Kong Polytechnic University Shenzhen Research Institute, Shenzhen, China. 5. Department of Applied Biology and Chemical Technology, Institute of Modern Chinese Medicine, The Hong Kong Polytechnic University, Hung Hom, Hong Kong, China. 6. International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Chinese Ministry of Education (MOE), Jinan University College of Pharmacy, Guangzhou, China.
Abstract
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.
BACKGROUND AND PURPOSE:Cerebral vasospasm and neuronal apoptosis after subarachnoid haemorrhage (SAH) is the major cause of morbidity and mortality in SAHpatients. 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 nitrateMN-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 rabbitSAH 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.
Authors: Federico E Rey; Xiao-Chun Li; Oscar A Carretero; Jeffrey L Garvin; Patrick J Pagano Journal: Circulation Date: 2002-11-05 Impact factor: 29.690
Authors: S M Ametamey; M Bruehlmeier; S Kneifel; M Kokic; M Honer; M Arigoni; A Buck; C Burger; S Samnick; G Quack; P A Schubiger Journal: Nucl Med Biol Date: 2002-02 Impact factor: 2.408