The effect of glutamate receptor blockers on glutamate release following spinal cord injury. Lack of evidence for an ongoing feedback cascade of damage --> glutamate release --> damage --> glutamate release --> etc.
It is widely hypothesized that excitotoxicity of released glutamate following a CNS insult is propagated by the cyclic cascade: glutamate release --> damage --> glutamate release --> further damage --> etc. We tested this hypothesis by determining the effects of attempting to interrupt the loop by administering glutamate receptor antagonists and Na(+)-channel blockers on glutamate release following spinal cord injury (SCI). The effects of administering the NMDA receptor blockers MK-801 and memantine, the AMPA/kainate receptor blockers NBQX and GYKI 52466, the AMPA receptor desensitization blocker cyclothiazide and the sodium channel blockers riluzole, mexiletine and QX-314 on post-SCI were determined. Agents were administered into the site of injury by direct injection, by microdialysis or systemically. None of these agents had an appreciable effect on glutamate release following SCI. Thus, it is unlikely that the above cascade produces significant secondary glutamate release and ongoing damage following SCI, although such cascades may worsen other CNS insults. We attribute our results to overwhelming effects of much greater release by direct mechanical damage and reversal of transport following SCI.
McAdoo
David J
DJ
Department of Neuroscience and Cell Biology, University of Texas Medical Branch, 301 University Boulevard, Galveston, TX 77555-1043, USA. djmcadoo@utmb.edu
Hughes
Michael G
MG
Nie
Linghui
L
Shah
Bhavin
B
Clifton
Cannon
C
Fullwood
Steven
S
Hulsebosch
Claire E
CE
D000818:Animals; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D025461:Feedback, Physiological / Q000187:drug effects*; D018698:Glutamic Acid / Q000378:metabolism*; D008297:Male; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D017470:Receptors, Glutamate / Q000187:drug effects*; D016037:Single-Blind Method; D026941:Sodium Channel Blockers / Q000494:pharmacology; D013116:Spinal Cord / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D013119:Spinal Cord Injuries / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology
D018691:Excitatory Amino Acid Antagonists; D017470:Receptors, Glutamate; D026941:Sodium Channel Blockers; D018698:Glutamic Acid