The neuropathological outcome associated with abnormal activation of glutamate receptors specific for N-methyl-D-aspartate (NMDA) has been implicated in stroke and in a variety of neurodegenerative disorders. The modulation of NMDA receptor-mediated function by endogenous factors may have profound implications in the outcome of glutamate neurotoxicity. Experiments outlined in this proposal are aimed at evaluating the role of a novel modulatory site on the NMDA receptor which is sensitive to sulfhydryl redox reagents. Since the injurious sequelae accompanying cerebral ischemia/reperfusion injury involve changes in redox equivalents, including the generation of oxygen free radicals, this modulatory site on the NMDA receptor may be intimately involved with the outcome of stroke.
The specific aims of these studies are: (1) to establish the actions of oxygen free radicals on the redox modulatory site of the NMDA receptor, (2)to study the effects of the essential nutrient pyrroloquinoline quinone (PQQ) on the redox modulatory site of the NMDA receptor, (3)to study the action of """"""""reactive"""""""" disulfide compounds on the NMDA receptor, and (4) to examine the kinetic changes in NMDA receptor function following chemical modifications with sulfhydryl redox reagents. The experiments outlined in this proposal utilized a well-defined culture system of rat cerebral cortex. Electrophysiological studies utilizing patch-clamp technology will be combined with intracellular calcium determinations, radioactive ligand binding, and neurotoxicity assays to achieve the proposed aims. The studies planned here will provide a more accurate picture of the events accompanying ischemia/reperfusion injury in the central nervous system, especially as they pertain to NMDA receptor function. Investigations aimed at these processes could lead to better prevention programs as well as to improved treatments for stroke. In addition, these studies may lead to the discovery of probes that may specifically label the NMDA receptor and aid in its biochemical characterization.
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