Mechanismen und Bedeutung der oxidativen Glutamattoxizität

Abstract

Neuronal cell death in diverse neurological disorders including ischemic stroke and neurodegenerative diseases can in part be attributed to excitotoxicity, where excessive glutamate release overstimulates ionotropic glutamate receptors resulting in massive calcium influx and cell death. Increased extracellular glutamate, however, also leads to a more prolonged cell death by oxidative glutamate toxicity. Here, increased extracellular glutamate depletes cells of cystine by blocking the glutamate/cystine antiporter Xc-. Cystine is required for the synthesis of the important antioxidant glutathione. The sequence of events leading to cell death after depletion of intracellular glutathione, involves the activation of 12-lipoxygenase, the accumulation of intracellular peroxides, and the activation of a cyclic GMP-dependent calcium channel close to the end of the death cascade. We review the mechanisms leading to cell death and discuss the relevance of this paradigm in vivo and as a method for the identification of novel neuroprotective proteins and signaling pathways.