Affiliations: Department of Neurology, Charité Hospital,
Humboldt University, Berlin, Germany
Note: [] Corresponding author: U. Dirnagl, Department of Neurology,
Charité Hospital, Schumannstr. 20-21, 10098 Berlin, Germany. Tel.: + 49
30 2802 8318; Fax: +49 30 2802 5047; E-mail: ulrich.dirnagl@charite.de
Abstract: It is well established that excitotoxicity is a key mechanism of
tissue destruction in focal cerebral ischemia (stroke). Very soon after onset
of a critical perfusion deficit energy failure leads to neuronal depolarization
and release of excitatory aminoacids, most notably glutamate. At the same time,
energy dependent reuptake of excitatory amino acids is impede. Overstimulation
of glutamate receptors (NMDA, AMPA/kainate, metabotropic) induces dramatically
increased intracellular Ca2+ concentrations, release of K+ into the
extracellular space, and cell swelling due to the passive movement of water
with Na+ influx. The massively increased intracellular second messenger Ca2+
triggers numerous deleterious processes, including free radial formation 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, and pointed to very
effective experimental treatment strategies, many of which involve the blockade
of glutamate receptors. Unfortunately, large clinical studies were so far
unable to replicate the animal data in human stroke patients. This article, by
reviewing excitotoxic damage of focal cerebral ischemia in the context of a
complex pathophysiological cascade, aims at explaining this failure and
stimulating further efforts in drug design and clinical evaluation to establish
the first neuroprotective therapy of human stroke.
