Glutamate as a neurotoxin

Abstract

Glutamate (Glu) is the major excitatory neurotransmitter in the mammalian central nervous system (CNS). Excessive glutamate in the extracellular space can trigger passive and active forms of neuronal death in the CNS via excessive activation of glutamate receptors. This phenomenon has been named excitotoxicity. Excitotoxicity has been implicated in the pathogenesis of acute and chronic neurodegenerative disorders. However, despite overwhelming preclinical data, human clinical trials in stroke or traumatic brain injury with antiexcitotoxic compounds acting at different levels of the excitotoxic cascade have failed to provide the expected neuroprotective effect. Here we present a focused overview of excitotoxic research including physiology of glutamate receptors and intracellular pathways leading to cell death. We review evidence for involvement of excitotoxicity in human neurodegenerative disorders and the results of several clinical trials. We present the most recent trends in the development of antiexcitotoxic therapies and also briefly refer to the hypothesis that interference with the trophic actions of glutamate in the context of CNS injuries may be one of the reasons why clinical trials with antiexcitotoxic compounds have failed.