Glutamate antagonists in therapy of stroke

It is well established that excitotoxicity is a key mechanism of tissue des truction in focal cerebral ischemia (stroke). Very soon after onset of a cr itical perfusion deficit energy failure leads to neuronal depolarization an d release of excitatory aminoacids, most notably glutamate. At the same tim e, energy dependent reuptake of excitatory amino acids is impede. Overstimu lation of glutamate receptors (NMDA, AMPA/kainte, metabotropic) induces dra matically incraesed intracellular Ca2+ concentrations; release of K+ into t he extracellular space, and cell swelling due to the passive movement of wa ter with Na+ influx. The massively increased intracellular second messenger Ca2+ triggers numerous deleterious processes, including free radial format ion and membrane degradation, mitochondrial dysfunction, inflammation, DNA- damage and apoptosis, A plethora of experimental studies have convincingly demonstrated the relevance of excitotoxicity in focal cerebral ischemia, an d pointed to very effective experimental treatment strategies, many of whic h involve the blockade of glutamate receptors. Unfortunately, large clinica l studies were so far unable to replicate the animal data in human stroke p atients. This article, by reviewing excitotoxic damage of focal cerebral is chemia in the context of a complex pathophysiological cascade, aims at expl aining this failure and stimulating furth er efforts in drug design and cli nical evaluation to establish the first neuroprotective therapy of human st roke.