Chen H S, Pellegrini J W, Aggarwal S K, Lei S Z, Warach S, Jensen F E, Lipton S A
Department of Neurology, Children's Hospital, Boston, Massachusetts.
J Neurosci. 1992 Nov;12(11):4427-36. doi: 10.1523/JNEUROSCI.12-11-04427.1992.
Excessive activation of NMDA receptors is thought to mediate the calcium-dependent neurotoxicity associated with hypoxic-ischemic brain injury, trauma, epilepsy, and several neurodegenerative diseases. For this reason, various NMDA antagonists have been investigated for their therapeutic potential in these diseases, but heretofore none have proven to be both effective and safe. In the present study, memantine, an adamantane derivative similar to the antiviral drug amantadine, is shown to block the channels activated by NMDA receptor stimulation. From whole-cell and single-channel recording experiments, the mechanism of action of memantine is deduced to be open-channel block, similar to MK-801; however, unlike MK-801, memantine is well tolerated clinically. Compared to MK-801, memantine's safety may be related to its faster kinetics of action with rapid blocking and unblocking rates at low micromolar concentrations. Furthermore, at these levels memantine is an uncompetitive antagonist and should theoretically allow near-normal physiological NMDA activity throughout the brain even in the face of pathologically high focal concentrations of glutamate. These pharmacological properties confer upon memantine a therapeutic advantage against NMDA receptor-mediated neurotoxicity with few side effects compared with other organic NMDA open-channel blockers. Moreover, memantine is increasingly effective against escalating levels of glutamate, such as those observed during a stroke. Low micromolar concentrations of memantine, levels known to be tolerated by patients receiving the drug for the treatment of Parkinson's disease, prevent NMDA receptor-mediated neurotoxicity in cultures of rat cortical and retinal ganglion cell neurons; memantine also appears to be both safe and effective in a rat stroke model. These results suggest that memantine has considerable therapeutic potential for the myriad of clinical entities associated with NMDA receptor-mediated neurotoxicity.
N-甲基-D-天冬氨酸（NMDA）受体的过度激活被认为介导了与缺氧缺血性脑损伤、创伤、癫痫以及几种神经退行性疾病相关的钙依赖性神经毒性。因此，人们对各种NMDA拮抗剂在这些疾病中的治疗潜力进行了研究，但迄今为止，尚无一种被证明是既有效又安全的。在本研究中，美金刚，一种与抗病毒药物金刚烷胺类似的金刚烷衍生物，被证明可阻断由NMDA受体刺激激活的通道。从全细胞和单通道记录实验中，推断美金刚的作用机制为开放通道阻断，类似于MK-801；然而，与MK-801不同的是，美金刚在临床上耐受性良好。与MK-801相比，美金刚的安全性可能与其更快的作用动力学有关，在低微摩尔浓度下具有快速的阻断和解阻断速率。此外，在这些浓度水平下，美金刚是一种非竞争性拮抗剂，理论上即使面对病理性高浓度的局部谷氨酸，也应能使整个大脑的NMDA生理活性接近正常。这些药理学特性赋予美金刚相对于其他有机NMDA开放通道阻滞剂在对抗NMDA受体介导的神经毒性方面的治疗优势，且副作用较少。此外，美金刚对不断升高的谷氨酸水平（如中风期间观察到的水平）越来越有效。低微摩尔浓度的美金刚，即接受该药物治疗帕金森病的患者已知可耐受的浓度，可预防大鼠皮质和视网膜神经节细胞神经元培养物中NMDA受体介导的神经毒性；美金刚在大鼠中风模型中似乎也是安全有效的。这些结果表明，美金刚对于与NMDA受体介导的神经毒性相关的众多临床病症具有相当大的治疗潜力。
