title: Excitotoxicity in neurological disorders--the glutamate paradox.
abstract: Beneficial effects of glutamate-receptor antagonists in models of neurological disorders are often used to support the notion that endogenous excitotoxicity (i.e. resulting from extracellular accumulation of endogenous glutamate) is a major contributor to neuronal death associated with these conditions. However, this interpretation conflicts with a number of robust and important experimental evidence. Here, emphasis is placed on two key elements: (i) very high extracellular levels of glutamate must be reached to initiate neuronal death, far above those measured in models of neurological disorders; and (ii) changes in extracellular glutamate as measured by microdialysis are not related to changes in the synaptic cleft, i.e. the compartment where neurotransmitter glutamate interacts with its receptors. It has become clear that the diversity and complexity of glutamate-mediated processes allow for a wide range of potential abnormalities (e.g. loss of selectivity of glutamate-operated ion channels, abnormal modulation of glutamate receptors). In addition, as neuronal death subsequent to ischemia and other insults is likely to result from multifactorial processes that may be inter-related, inhibition of glutamate-mediated synaptic transmission may be neuroprotective by increasing the resistance of neurons to other deleterious mechanisms (e.g. inadequate energy supply) that are not directly related to glutamatergic transmission.
authors.affiliation: Pharmacology, School of Pharmacy, University of Bradford, Bradford, UK.t.obrenovitch@bradford.ac.uk
authors.forename: T P
authors.initials: TP
authors.lastname: Obrenovitch
authors.forename: J
authors.initials: J
authors.lastname: Urenjak
authors.forename: E
authors.initials: E
authors.lastname: Zilkha
authors.forename: T M
authors.initials: TM
authors.lastname: Jay
mesh_terms: D000818:Animals; D016923:Cell Death / Q000502:physiology; D018698:Glutamic Acid / Q000633:toxicity*; D009422:Nervous System Diseases / Q000378:metabolism*; D009474:Neurons / Q000166:cytology* / Q000378:metabolism*; D009498:Neurotoxins / Q000378:metabolism*
chemical_list: D009498:Neurotoxins; D018698:Glutamic Acid