Elsevier

Brain Research

Volume 451, Issues 1–2, 7 June 1988, Pages 205-212
Brain Research

Glutamate becomes neurotoxic via the N-methyl-d-aspartate receptor when intracellular energy levels are reduced

https://doi.org/10.1016/0006-8993(88)90765-2Get rights and content

Abstract

The N-methyl-d-aspartate (NMDA) subtype of glutamate receptor appears to play a pivotal role in enabling glutamate to express its neurotoxic potential in a variety of neurological disorders. Our result show that the transition of glutamate from neurotransmitter to neurotoxin is facilitated when cellular energy is limited in cultured cerebellar neurons. Omission of glucose, exclusion of oxygen, or inclusion of inhibitors of oxidative phosphorylation or the sodium/potassium pump, enables the excitatory amino acids glutamate or NMDA to express their neurotoxic potential. We interpret these results as demonstrating that glucose metabolism, ATP production, and functioning Na+, K+-ATPases are necessary to generate a resting potential sufficient to maintain the voltage-dependent Mg2+ block of the NMDA receptor channel; relief of the Mg2+ block enables the excitatory amino acids to act persistently at the NMDA receptor, resulting in the opening of ion channels and subsequent neuronal damage. These findings are discussed in the context fo perturbations or abnormalities which lead to decreased availability or utilization of glucose and oxygen in the brain which may trigger endogenous excitatory amino acids to become neurotoxic by this mechanism.

Reference (40)

  • BarnesD.M.

    Drug may protect brains of heart attack victims

    Science

    (1987)
  • BerdicheveskyE.N. et al.

    Kainate, N-methyl-d-aspartate and other excitatory amino acids increase calcium influx into rat brain cortex cells in vitro

    Neurosci. Lett.

    (1983)
  • ButcherS.B. et al.

    Cellular origins of endogenous amino acids released into the extracellular fluid of the cat striatum during severe insulin-induced hypoglycemia

    J. Neurochem.

    (1987)
  • ChoiD.W. et al.

    Glutamate neurotoxicity in cortical cell culture

    J. Neurosci.

    (1987)
  • CoyleJ.T.

    Neurotoxic action of kainic acid

    J. Neurochem.

    (1983)
  • CoyleJ.T. et al.

    Lesion of striatal neurons with kainic acid provides a model for Huntington's chorea

    Nature (Lond.)

    (1976)
  • Cull-CandyS.G. et al.

    Multiple-conductance channels activated by excitatory amino acids in cerebellar neurons

    Nature (Lond.)

    (1987)
  • DrejerJ. et al.

    Cellular origin of ischemia-induced glutamate release from brain tissue in vivo and in vitro

    J. Neurochem.

    (1985)
  • HodgkinA.L. et al.

    Active transport of cations in giant axons fromSepia andLoligo

    J. Physiol. (Lond.)

    (1955)
  • JahrC.E. et al.

    Glutamate activates multiple single channel conductances in hippocampal neurons

    Nature (Lond.)

    (1987)
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