White matter injury in spinal cord ischemia: protection by AMPA/kainate glutamate receptor antagonism.
OBJECTIVE
Spinal cord ischemia is a serious complication of surgery of the aorta. NMDA receptor activation secondary to ischemia-induced release of glutamate is a major mechanism of neuronal death in gray matter. White matter injury after ischemia results in long-tract dysfunction and disability. The AMPA/kainate receptor mechanism has recently been implicated in white matter injury.


METHODS
We studied the effects of AMPA/kainate receptor blockade on ischemic white matter injury in a rat model of spinal cord ischemia.


RESULTS
Intrathecal administration of an AMPA/kainate antagonist, 6-nitro-7-sulfamoyl-(f)-quinoxaline-2, 3-dione (NBQX), 1 hour before ischemia reduced locomotor deficit, based on the Basso-Beattie-Bresnahan scale (0=total paralysis; 21=normal) (sham: 21+/-0, n=3; saline: 3.7+/-4.5, n=7; NBQX: 12. 7+/-7.0, n=7, P<0.05) 6 weeks after ischemia. Gray matter damage and neuronal loss in the ventral horn were evident after ischemia, but no difference was noted between the saline and NBQX groups. The extent of white matter injury was quantitatively assessed, based on axonal counts, and was significantly less in the NBQX as compared with the saline group in the ventral (sham: 1063+/-44/200x200 microm, n=3; saline: 556+/-104, n=7; NBQX: 883+/-103, n=7), ventrolateral (sham: 1060+/-135, n=3; saline: 411+/-66, n=7; NBQX: 676+/-122, n=7), and corticospinal tract (sham: 3391+/-219, n=3; saline: 318+/-23, n=7; NBQX: 588+/-103, n=7) in the white matter on day 42.


CONCLUSIONS
Results indicate severe white matter injury in the spinal cord after transient ischemia. NBQX, an AMPA/kainate receptor antagonist, reduced ischemia-induced white matter injury and improved locomotor function.
Division of Cardiothoracic Surgery, Department of Surgery, Washington University School of Medicine, St. Louis, MO 63110, USA.
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GK
Kanellopoulos
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Xu
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Hsu
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T M
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Sundt
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Kouchoukos
D000818:Animals; D000870:Anterior Horn Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D001369:Axons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D001522:Behavior, Animal / Q000187:drug effects; D002452:Cell Count; D018691:Excitatory Amino Acid Antagonists / Q000008:administration & dosage*; D006614:Hindlimb / Q000294:innervation / Q000503:physiopathology; D007278:Injections, Spinal; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D011810:Quinoxalines / Q000008:administration & dosage*; D051381:Rats; D020318:Rats, Long-Evans; D018091:Receptors, AMPA / Q000037:antagonists & inhibitors* / Q000378:metabolism; D020127:Recovery of Function; D020760:Spinal Cord Ischemia / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*
D018691:Excitatory Amino Acid Antagonists; D011810:Quinoxalines; D018091:Receptors, AMPA; C062865:2,3-dioxo-6-nitro-7-sulfamoylbenzo(f)quinoxaline