Protective effect of MK-801 on the anoxia-aglycemia induced damage in the fluorocitrate-treated hippocampal slice of the rat.
We investigated electrophysiological responses induced by ischemia-like insult (anoxia and aglycemia, AA) in the rat hippocampal CA1 pyramidal cells in an in vitro slice preparation devoid of glial metabolism. In the slice treated with fluorocitrate (100 microM), a glia-specific metabolic inhibitor, 10 min AA induced hyperexcitation as evidenced by an appearance of multiple population spikes evoked by stimulation of the Schaffer collateral/commissural pathway in the CA1 region prior to elimination of the response. Readministration of oxygen and glucose failed to restore the population spike amplitude. Intracellular recordings revealed that 10 min AA induced slow EPSPs with relative long duration. The induction of the slow EPSPs was followed by a rapid membrane depolarization with a large amplitude. When the fluorocitrate-treated slice was exposed to MK-801 (10 microM), a non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist, 10 min AA failed to induce either the hyperexcitation of synaptic responses or the rapid depolarization. Furthermore, synaptic responses were fully restored after readministration of oxygen and glucose. In contrast, neither the synaptic hyperexcitation nor the rapid depolarization was observed during 10 min AA in the hippocampal CA1 pyramidal cells of the control slice. In addition, an irreversible synaptic failure associated with AA was not induced in the control slice. These results strongly suggest that fluorocitrate increases NMDA receptor-dependent AA-induced damage in the hippocampal slice by interfering glial spatial buffering of K+.
Nakanishi
H
H
Department of Pharmacology, Faculty of Dentistry, Kyushu University, Fukuoka, Japan. nakandeg@mbox.nc.kyushu-u.ac.jp
Kawachi
A
A
Okada
M
M
Fujiwara
M
M
Yamamoto
K
K
D000818:Animals; D002545:Brain Ischemia; D002951:Citrates / Q000633:toxicity*; D016291:Dizocilpine Maleate / Q000494:pharmacology*; D005071:Evoked Potentials / Q000187:drug effects; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D006624:Hippocampus / Q000473:pathology / Q000503:physiopathology*; D002534:Hypoxia, Brain / Q000503:physiopathology* / Q000517:prevention & control; D066298:In Vitro Techniques; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D009457:Neuroglia / Q000187:drug effects / Q000502:physiology*; D018696:Neuroprotective Agents / Q000494:pharmacology; D017966:Pyramidal Cells / Q000187:drug effects / Q000473:pathology / Q000502:physiology*; D051381:Rats; D017208:Rats, Wistar; D009435:Synaptic Transmission / Q000187:drug effects
D002951:Citrates; D018691:Excitatory Amino Acid Antagonists; D018696:Neuroprotective Agents; C007744:fluorocitrate; D016291:Dizocilpine Maleate