Molecular mechanisms of glutamate-dependent neurodegeneration in ischemia and traumatic brain injury |
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Authors: | M?Arundine Email author" target="_blank">M?TymianskiEmail author |
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Institution: | (1) Toronto Western Hospital Research Institute, 399 Bathurst St., M5T 2S8 Toronto, Ontario, Canada;(2) Department of Physiology, University of Toronto, M5G 1X8 Toronto, Ontario, Canada |
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Abstract: | Stroke and neurotrauma mediate neuronal death through a series of events that involve multiple interdependent molecular pathways. It has been suggested that these pathways are triggered following elevations in extracellular excitatory amino acids, primarily glutamate 1]. This report outlines mechanisms involving glutamate-mediated excitotoxicity with specific focus on (i) the role of Ca2+ in neurotoxicity, (ii) The concept of source specificity of neurotoxicity, (iii) the role of the ionotropic N-methyl-D-aspartate (NMDA)-subtype glutamate receptor and its associated submembrane molecules that may give rise to signaling specificity in excitotoxicity and (iv) the role of glutamate-mediated free-radical generation and associated cell death pathways. We also highlight a novel, peptide-based approach for uncoupling NMDA receptors from excitotoxicity in the rat central nervous system subjected to focal ischemia, thereby reducing stroke infarct volume and improving neurological functioning.Received 11 August 2003; received after revision 15 September 2003; accepted 17 September 2003 |
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Keywords: | Glutamate NMDA receptor calcium nitric oxide ROS ischemia traumatic brain injury postsynaptic density protein-95 superoxide |
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