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Protection by MK-801 against hypoxia-, excitotoxin-, and depolarization-induced neuronal damage in vitro
A Schurr1, R S Payne, B M Rigor
1Department of Anesthesiology, University of Louisville, School of Medicine, KY 40292, USA.
Abstract:
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.
Insights
Hypoxia causes mild brain damage, but kainate or AMPA dramatically worsens it. MK-801, an NMDA antagonist, unexpectedly protected against this enhanced hypoxic damage, suggesting novel mechanisms beyond NMDA receptor blockade.
Area of Science:
- Neuroscience
- Neuroprotection
- Neuropharmacology
Background:
- Hypoxia induces neuronal damage in rat hippocampal slices.
- Excitotoxins like kainate and AMPA exacerbate hypoxic neuronal injury.
- NMDA receptor antagonists are investigated for neuroprotective effects.
Purpose of the Study:
- To investigate the synergistic effect of kainate/AMPA and hypoxia on neuronal damage.
- To evaluate the efficacy of NMDA receptor antagonists in mitigating this enhanced damage.
- To explore the mechanism of action of MK-801 in neuroprotection during hypoxia.
Main Methods:
- Rat hippocampal slices were subjected to hypoxia alone or combined with kainate/AMPA.
- Neuronal function recovery (CA1-evoked population spike) was measured after a recovery period.
- The effects of antagonists GYKI 52466 (kainate/AMPA antagonist), APV (NMDA antagonist), and MK-801 (noncompetitive NMDA antagonist) were assessed.
Main Results:
- Hypoxia alone caused mild damage (72% recovery), but kainate/AMPA significantly increased damage (6-15% recovery).
- GYKI 52466 dose-dependently attenuated kainate/AMPA-enhanced hypoxic damage.
- MK-801 unexpectedly showed greater efficacy than GYKI 52466 in attenuating this damage, even under conditions blocking NMDA receptor binding.
Conclusions:
- MK-801's neuroprotective effects against kainate/AMPA-enhanced hypoxic damage extend beyond NMDA receptor antagonism.
- MK-801 may exert its antihypoxic effects through blockade of L-type calcium channels.
- Further investigation into MK-801's interaction with calcium channels is warranted.