McAdoo David J, Hughes Michael G, Nie Linghui, Shah Bhavin, Clifton Cannon, Fullwood Steven, Hulsebosch Claire E
Department of Neuroscience and Cell Biology, University of Texas Medical Branch, 301 University Boulevard, Galveston, TX 77555-1043, USA.
Brain Res. 2005 Mar 15;1038(1):92-9. doi: 10.1016/j.brainres.2005.01.024.
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.
人们普遍推测，中枢神经系统损伤后释放的谷氨酸的兴奋性毒性是通过循环级联反应传播的：谷氨酸释放→损伤→谷氨酸释放→进一步损伤→等等。我们通过确定给予谷氨酸受体拮抗剂和钠通道阻滞剂以试图中断该循环对脊髓损伤（SCI）后谷氨酸释放的影响来检验这一假设。测定了给予NMDA受体阻滞剂MK - 801和美金刚、AMPA/海人酸受体阻滞剂NBQX和GYKI 52466、AMPA受体脱敏阻滞剂环噻嗪以及钠通道阻滞剂利鲁唑、美西律和QX - 314对SCI后的影响。通过直接注射、微透析或全身给药将药物注入损伤部位。这些药物均未对SCI后的谷氨酸释放产生明显影响。因此，上述级联反应不太可能在SCI后产生显著的继发性谷氨酸释放和持续损伤，尽管这种级联反应可能会加重其他中枢神经系统损伤。我们将我们的结果归因于SCI后直接机械损伤导致的大量释放以及转运逆转的压倒性影响。
