Neuroprotectants targeting NMDA receptor signaling

Abstract

N-Methyl-D-aspartate (NMDA) receptors are key mediators of fast excitatory synaptic transmission within the mammalian central nervous system (CNS) and play vital roles in learning, memory, and synaptic development. Overactivation of NMDA receptors (NMDARs) at glutamatergic synapses often results in excitotoxicity, which can cause neuronal injury and death, and is associated with many neurological disorders such as ischemic stroke, epilepsy, neuropathic pain, traumatic brain and spinal injuries; ocular disorders such as glaucoma; as well as neurodegenerative diseases, including amyotrophic lateral sclerosis, Parkinson's, Huntington's, and Alzheimer's diseases. Numerous NMDAR antagonists have been developed that have been effective in reducing cell damage and death in both in vitro and in vivo experimental models of neurological disease, such as ischemia and traumatic brain injury. Unfortunately, clinical use of these NMDAR antagonists has been limited by intolerable side effects, likely due to the necessity of NMDARs in normal brain function. Intracellular signaling pathways that couple to NMDAR activation can promote either cell survival or cell death, depending on NMDAR subunit composition and/or subcellular localization. Ideal therapeutic strategies targeting NMDAR-mediated neurotoxicity should selectively block pro-death signaling, while sparing pro-survival signals. Neuroprotectants targeting downstream effectors of NMDAR-mediated cell death, rather than NMDARs directly, would maintain normal NMDAR function and minimize adverse effects commonly associated with traditional NMDAR antagonists in the treatment of neurological disorders.