Why do many NMDA antagonists fail, while others are safe and effective at blocking excitotoxicity associated with dementia and acute injury?

Similar to drug development programs for stroke and traumatic brain injury, programs developed for Alzheimer's disease (AD) have not been very effective in treating dementia. Recently, researchers have explored modulating excitatory synaptic neurotransmission via the N-methyl-D-aspartate receptor (NMDAR) to treat AD. However, many investigators doubt that NMDA antagonists are safe and effective for treating persons with AD because they have failed in stroke and trauma programs. This article explores the role of NMDA-mediated excitotoxicity in AD, reviews how the NMDAR functions, highlights the side effects and alternate signaling pathways that are initiated from NMDAR activation, provides examples of NMDA antagonists that do not exhibit the typical side effects, and discusses why some NMDA antagonist compounds are effective and safe in limiting cascades of excitotoxicity in dementia or acute brain injury.