Molecular mechanisms of glutamate-dependent neurodegeneration in ischemia and traumatic brain injury

Cell Mol Life Sci. 2004 Mar;61(6):657-68. doi: 10.1007/s00018-003-3319-x.


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 Ca(2+) 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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.
  • Review

MeSH terms

  • Animals
  • Brain Injuries / metabolism*
  • Brain Injuries / pathology
  • Brain Ischemia / metabolism*
  • Brain Ischemia / pathology
  • Glutamic Acid / metabolism*
  • Humans
  • N-Methylaspartate / metabolism
  • Nerve Degeneration / metabolism*
  • Receptors, Glutamate / metabolism
  • Receptors, N-Methyl-D-Aspartate / metabolism


  • Receptors, Glutamate
  • Receptors, N-Methyl-D-Aspartate
  • Glutamic Acid
  • N-Methylaspartate