Protection by MK-801 against hypoxia-, excitotoxin-, and depolarization-induced neuronal damage in vitro.
Exposure of rat hippocampal slices to 12-min hypoxia produced only mild neuronal damage, as 72% of all slices recovered their CA1-evoked population spike following a 30-min recovery period. However, when this hypoxic insult was administered in the presence of 2.5 microM kainate or AMPA, only 6 and 15% of the slices, respectively, recovered their neuronal function. This enhancement of hypoxic damage by kainate could be attenuated in a dose-dependent fashion by the kainate/AMPA antagonist GYKI 52466 but not by the competitive NMDA antagonist APV. Unexpectedly, the noncompetitive NMDA antagonist MK-801 also attenuated the kainate- and AMPA-enhanced hypoxic neuronal damage and was more efficacious than GYKI 52466. Considering (1) the ability of MK-801 to antagonize hypoxic neuronal damage in the absence or the presence of NMDA, kainate or AMPA; (2) the antihypoxic effect of MK-801 in the presence of APV + 7-chlorokynurenate, a pairing that supposedly blocks MK-801 binding to the NMDA receptor; (3) the ability of MK-801 to protect hippocampal slices against brain damage induced by depolarization + excitotoxin (50 mM KCl + mM glutamate for 60 min); and (4) the ability of diltiazem, an L-type calcium channel blocker, to protect hippocampal slices against hypoxic neuronal damage, we conclude that the mode of action of MK-801 cannot be explained by its NMDA receptor antagonistic properties alone. A possible blockade of Ca2+ channels, most likely of the L-type, by MK-801 should be considered along with other mechanisms.
D015763:2-Amino-5-phosphonovalerate / Q000494:pharmacology*; D014151:Anti-Anxiety Agents; D001569:Benzodiazepines / Q000494:pharmacology; D004110:Diltiazem / Q000494:pharmacology; D016291:Dizocilpine Maleate / Q000494:pharmacology*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects*; D002534:Hypoxia, Brain / Q000473:pathology / Q000517:prevention & control*; D066298:In Vitro Techniques; D007736:Kynurenic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D008564:Membrane Potentials / Q000187:drug effects; D009474:Neurons / Q000187:drug effects*; D009543:Nifedipine / Q000494:pharmacology; D010875:Pipecolic Acids / Q000494:pharmacology; D018009:Receptors, Glycine / Q000037:antagonists & inhibitors; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / Q000037:antagonists & inhibitors / Q000494:pharmacology
D014151:Anti-Anxiety Agents; D018691:Excitatory Amino Acid Antagonists; D010875:Pipecolic Acids; D018009:Receptors, Glycine; D016194:Receptors, N-Methyl-D-Aspartate; C061950:GYKI 52466; D001569:Benzodiazepines; C053672:selfotel; D016291:Dizocilpine Maleate; D015763:2-Amino-5-phosphonovalerate; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; D004110:Diltiazem; D007736:Kynurenic Acid; D009543:Nifedipine; C057013:7-chlorokynurenic acid