Novel injury mechanism in anoxia and trauma of spinal cord white matter: glutamate release via reverse Na+-dependent glutamate transport.
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 microm) 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.
Loeb Health Research Institute, Ottawa Hospital, University of Ottawa, Ottawa, Ontario, Canada, K1Y 4K9.
S
S
Li
G A
GA
Mealing
P
P
Morley
P K
PK
Stys
D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000200:Action Potentials; D027322:Amino Acid Transport System X-AG; D000818:Animals; D001369:Axons / Q000473:pathology; D002352:Carrier Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D015687:Cell Hypoxia; D050491:Glutamate Plasma Membrane Transport Proteins; D018698:Glutamic Acid / Q000378:metabolism*; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D008297:Male; D009186:Myelin Sheath / Q000473:pathology; D018408:Patch-Clamp Techniques; D011312:Pressure; D051381:Rats; D020318:Rats, Long-Evans; D018091:Receptors, AMPA / Q000037:antagonists & inhibitors / Q000502:physiology; D012964:Sodium / Q000502:physiology*; D013116:Spinal Cord / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D013119:Spinal Cord Injuries / Q000209:etiology / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D013314:Stress, Mechanical; D027981:Symporters
D018528:ATP-Binding Cassette Transporters; D027322:Amino Acid Transport System X-AG; D002352:Carrier Proteins; D050491:Glutamate Plasma Membrane Transport Proteins; D018091:Receptors, AMPA; D027981:Symporters; D018698:Glutamic Acid; D012964:Sodium