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Na(+)-K(+)-ATPase inhibition and depolarization induce glutamate release via reverse Na(+)-dependent transport in spinal cord white matter.

Abstract
Excitotoxic mechanisms involving alpha-amino-3-hydroxy-5-methyl-isoxazole-4-propionate (AMPA)/kainate receptors play an important role in mediating cellular damage in spinal cord injury. However, the precise cellular mechanisms of glutamate release from non-synaptic white matter are not well understood. We examined how the collapse of transmembrane Na(+) and K(+) gradients induces reverse operation of Na(+)-dependent glutamate transporters, leading to glutamate efflux and injury to rat spinal dorsal columns in vitro. Compound action potentials were irreversibly reduced to 43% of control after ouabain/high K(+)/low Na(+) exposure (500 microM ouabain for 30 min to increase [Na(+)](i), followed by 1 h ouabain+high K(+) (129 mM)/low Na(+) (27 mM), to further reverse transmembrane ion gradients) followed by a 2 h wash. Ca(2+)-free perfusate was very protective (compound action potential amplitude recovered to 87% vs. 43%). The broad spectrum glutamate antagonist kynurenic acid (1 mM) or the selective AMPA antagonist GYKI52466 (30 microM) were partially protective (68% recovery). Inhibition of Na(+)-dependent glutamate transport with L-trans-pyrrolidine-2,4-dicarboxylic acid (1 mM) also provided significant protection (71% recovery), similar to that seen with glutamate receptor antagonists. Blocking reverse Na(+)-Ca(2+) exchange with KB-R7943 (10 microM) however, was ineffective in this paradigm (49% recovery). Semiquantitative glutamate immunohistochemistry revealed that levels of this amino acid were significantly depleted in axon cylinders and, to a lesser degree, in oligodendrocytes (but not in astrocytes) by ouabain/high K(+)/low Na(+), which was largely prevented by glutamate transport inhibition. Our data show that dorsal column white matter contains the necessary glutamate pools and release mechanisms to induce significant injury. When Na(+) and K(+) gradients are disrupted, even in the absence of reduced cellular energy reserves, reverse operation of Na(+)-dependent glutamate transport will release enough endogenous glutamate to activate AMPA receptors and cause substantial Ca(2+)-dependent injury. This mechanism likely plays an important role during ischemic and traumatic white matter injury, where collapse of transmembrane Na(+) and K(+) gradients occurs.
AuthorsS Li, P K Stys
JournalNeuroscience (Neuroscience) Vol. 107 Issue 4 Pg. 675-83 ( 2001) ISSN: 0306-4522 [Print] United States
PMID11720790 (Publication Type: Journal Article)
Chemical References
  • 2-(2-(4-(4-nitrobenzyloxy)phenyl)ethyl)isothiourea methanesulfonate
  • Anti-Anxiety Agents
  • Anti-Arrhythmia Agents
  • Dicarboxylic Acids
  • Enzyme Inhibitors
  • Excitatory Amino Acid Agonists
  • Excitatory Amino Acid Antagonists
  • Neurotransmitter Uptake Inhibitors
  • Pyrrolidines
  • Receptors, AMPA
  • GYKI 52466
  • Benzodiazepines
  • Glutamic Acid
  • Ouabain
  • alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid
  • pyrrolidine-2,4-dicarboxylic acid
  • Sodium
  • Sodium-Potassium-Exchanging ATPase
  • Thiourea
  • Kynurenic Acid
  • Potassium
  • Calcium
Topics
  • Animals
  • Anti-Anxiety Agents (pharmacology)
  • Anti-Arrhythmia Agents (pharmacology)
  • Benzodiazepines
  • Calcium (metabolism)
  • Dicarboxylic Acids (pharmacology)
  • Enzyme Inhibitors (pharmacology)
  • Excitatory Amino Acid Agonists (pharmacology)
  • Excitatory Amino Acid Antagonists (pharmacology)
  • Glutamic Acid (metabolism)
  • Kynurenic Acid (pharmacology)
  • Male
  • Membrane Potentials (drug effects, physiology)
  • Nerve Fibers, Myelinated (metabolism)
  • Neurotransmitter Uptake Inhibitors (pharmacology)
  • Ouabain (pharmacology)
  • Potassium (metabolism)
  • Pyrrolidines (pharmacology)
  • Rats
  • Rats, Long-Evans
  • Receptors, AMPA (metabolism)
  • Sodium (metabolism)
  • Sodium-Potassium-Exchanging ATPase (antagonists & inhibitors)
  • Spinal Cord (cytology, metabolism)
  • Thiourea (analogs & derivatives, pharmacology)
  • alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid (pharmacology)

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