NMDA receptor antagonists excitotoxicity

Among promising candidates as antidotes against CNS intoxication by OP nerve agents, memantine (MEM) has been shown to pose both anti-excitotoxic and anti-epileptic properties. Memantine is an uncompetitive NMDA receptor antagonist, clinically used for the treatment of Alzheimer s disease, Parkinson s disease and spasticity, in the absence of serious side effects (Ozsuer et al, 2005 Lipton, 2005). From a series of rat in vivo experiments, it is evident that pre-administration of memantine significantly protects... 

Already two decades ago, it was found that QUIN promotes excitotoxicity in vivo, and it was later suggested that these excitotoxic effects are mediated by QUIN s weak agonistic activity on the NMDA receptor, with an IC50 of 30-100 pM [1]. The observed lesions, as mediated by intracerebral injection of QUIN, can be prevented through the application of NMDA receptor antagonists, so it is indeed likely that the observed effects are mediated through NMDA receptor activation... 

Excitotoxic lesions generated in primates using NMDA receptor agonists such as quinolinic acid cause neuronal loss similar to that found in HD, emphasizing, the potential role of excitotoxicity in HD. Intrastriatal injections of the reversible succinate dehydrogenase inhibitor, malonate, into rats caused a decrease in ATP levels and increased lactate and excitotoxic lesions, which could be prevented by NMDA antagonists. 

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