The Journal of Neuroscience, 1999, 19:RC16:1-9
RAPID COMMUNICATION
Novel Injury Mechanism in Anoxia and Trauma of Spinal Cord White
Matter: Glutamate Release via Reverse Na+-dependent
Glutamate Transport
Shuxin
Li1,
Geoff A. R.
Mealing2,
Paul
Morley2, and
Peter K.
Stys1
1 Loeb Health Research Institute, Ottawa Hospital,
University of Ottawa, Ottawa, Ontario, Canada, K1Y 4K9, and
2 Institute for Biological Sciences, National Research
Council of Canada, Ottawa, Ontario, Canada K1A 0R6
Spinal cord injury is a devastating condition, with much of the
clinical disability resulting from disruption of white matter tracts.
Recent reports suggest a component of glutamate excitotoxicity in
spinal cord injury. In this study, the role of glutamate and mechanism
of release of this excitotoxin were investigated in rat dorsal column
slices subjected to 60 min of anoxia or 15 sec of mechanical
compression at a force of 2 gm in vitro. The
broad-spectrum glutamate antagonist kynurenic acid (1 mM)
and the selective AMPA antagonist GYKI52466 (30 µM) were
protective against anoxia (compound action potential amplitude
recovered to 56 vs 27% without drug). GYKI52466 was also effective
against trauma (65 vs 35%). Inhibition of
Na+-dependent glutamate transport with
dihydrokainate or
L-trans-pyrrolidine-2,4-dicarboxylic acid (1 mM each) protected against anoxia (65-75 vs 25%) and
trauma (70 vs 35%). The depletion of cytosolic glutamate in axon
cylinders and oligodendrocytes by anoxia was completely prevented by
glutamate transport inhibition. Immunohistochemistry revealed that a
large component of injury occurred in the myelin sheath and was
prevented by AMPA receptor blockade or glutamate transport inhibitors.
We conclude that release of glutamate by reversal of
Na+-dependent glutamate transport with subsequent
activation of AMPA receptors is an important mechanism in spinal cord
white matter anoxic and traumatic injury.
Key words:
spinal cord injury; axon; anoxia; trauma; AMPA; Na+-glutamate transport; myelin; dihydrokainate; L-trans-pyrrolidine-2,4-dicarboxylic acid; GYKI52466; kynurenic acid
Copyright © 1999 Society for Neuroscience 0270-6474/99/$05.00/0
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