Excitotoxicity in neurological disorders — the glutamate paradox

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  • T.P. Obrenovitch
    Pharmacology School of Pharmacy University of Bradford Bradford BD7 1DP UK
  • J. Urenjak
    Pharmacology School of Pharmacy University of Bradford Bradford BD7 1DP UK
  • E. Zilkha
    Pharmacology School of Pharmacy University of Bradford Bradford BD7 1DP UK
  • T.M. Jay
    Laboratoire de Neurobiologie de l'Apprentissage, de la Mémoire et de la Communication, CNRS‐UMR 8620, Université Paris‐Sud 91405 Orsay France

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<jats:title>Abstract</jats:title><jats:sec><jats:label /><jats:p>Beneficial effects of glutamate‐receptor antagonists in models of neurological disorders are often used to support the notion that <jats:italic>endogenous</jats:italic> 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.</jats:p><jats:p>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.</jats:p></jats:sec>

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