NMDA-gated ion channel research and its therapeutic potentials in neurodegenerative diseases: a review

Abstract

The N-methyl-D-aspartate (NMDA) subtype of glutamate receptor (NMDAR) is essential for normal function of the central nervous system (CNS). Classical NMDARs, activated by glycine and glutamate, are heteromultimers comprising NR1 and NR2 subunits. Nonetheless, excessive activation of NMDARs by excitatory amino acids such as glutamate is thought to mediate neuronal damage in many neurological disorders. The dual role of NMDARs in normal and abnormal functioning of the CNS imposes significant constraints on possible therapeutic strategies aimed at ameliorating neurodegenerative diseases. To create safe NMDAR-based therapies, blockade of excessive NMDAR activity must therefore be achieved with minimal interference on its normal neuronal function. In general, NMDAR antagonists can be classified pharmacologically according to the site of action on the receptor-channel complex. These include drugs acting at the agonist sites (NMDA and glycine), channel pore, and modulatory sites. Both competitive NMDA and glycine antagonists result in generalized inhibition of NMDAR activities and have, thus, failed in clinical trials. Open-channel blockers with uncompetitive antagonism and drugs modulating NMDAR activities are appealing therapeutic strategies because, in theory, these properties could decrease neurotoxicity due to excessive levels of glutamate while sparing physiological neurotransmission. We review here NMDAR-related research that may lead to future therapeutic intervention against neurotoxicity.