| Abstract | L-glutamate is the major excitatory amino acid in the brain of vertebrates. Glutamate plays important roles in fast synaptic transmission, neural development, neuronal plasticity, learning, and memory (Ozawa et al, 1998; Dingledine et al., 1999). However, the over stimulation of glutamate receptors is believed to initiate cellular processes leading to neurodegeneration (Rothman and Olney, 1986; Choi, 1988; Meldrum and Garthwaite, 1990). Glutamate mediates its physiological effects via ionotropic (iGluRs) and metabotropic receptors (mGluRs) (Dingledine et al., 1999). Postsynaptic ionotropic receptors are ligand-gated ion channels that are subdivided into the N-methyl-D-aspartate (NMDA), kainate (KA), and a-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) receptor subtypes according to the preferred agonist that activates the receptor (Dingledine et al, 1999). All ionotropic receptors are permeable to Na+ and K+, but only some are permeable to Ca2+. Each receptor type is composed of subunits encoded by at least six gene families. NMDA receptors are composed of NRl, NR2A-D, or NR3A and NR3B subunits; AMPA receptors by GluRl-4; and KA by KAl, KA2, and GluR5-7 subunits (Dingledine et al, 1999). Coassembly of subunits produces channels with different biophysical properties. mGluRs, which are localized both pre- and postsynaptically, are G-protein linked receptors that activate second messenger systems rather than gating ion channels (Sugiyama et al, 1987; Conn and Pin, 1997). Molecular cloning has identified at least eight subtypes (mGluRl-8) (Conn and Pin, 1997). Antagonists to the NMDA and AMPA receptors are neuroprotective in some animal models of neurodegenerative diseases including cerebral ischemia, epilepsy, Parkinson's, and Alzheimer's diseases (Small et al., 1999). While glutamate receptor antagonists have not yet been successful in the clinic due to difficulties with side-effects, the development of new glutamate receptor antagonists, used either alone or as part of combination therapy, may prove to be more successful. |
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