The N-methyl- d-aspartate antagonists aminophosphonovaleric acid and MK-801 reduce anoxic damage to dentate granule and CA1 pyramidal cells in the rat hippocampal slice

Abstract

The effect of the N-methyl- d-aspartate antagonists, aminophosphonovaleric acid and MK-801, on irreversible transmission loss subsequent to anoxia was examined using the hippocampal slice preparation. A population spike was recorded from either the dentate granule cells or the CA1 pyramidal cells and the amplitude of this spike was compared before and 60 min following anoxia. After 10 min of anoxia the dentate granule cells recovered to 16 ± 7% (mean ± SE) of their preanoxic level when untreated and to 54 ± 15% when treated with aminophosphonovaleric acid (APV). In slices treated with MK-801 the population spikes recorded from dentate granule cells recovered to 85 ± 4% of their preanoxic level after 10 min of anoxia. Untreated CA1 pyramidal cells recovered to 8 ± 3% of their preanoxic amplitude after 5 min of anoxia; they recovered to 59 ± 6% when treated with MK-801 and 31 ± 13% when treated with APV. The recovery of slices treated with the drugs was significantly different from that of untreated slices. ATP levels were measured in both the dentate and the CA1 region of slices. ATP in both regions fell less during anoxia when the slices were pretreated with either APV or MK-801. These differences between drug-treated and untreated tissue were significant with APV and MK-801 in dentate tissue after 10 min of anoxia and with MK-801 in CA1 tissue after 5 min of anoxia. This reduced fall in ATP during anoxia was accompanied by better physiological recovery after anoxia. We conclude that these NMDA antagonists provide protection against anoxic damage to dentate granule and CA1 pyramidal cells in this in vitro hippocampal preparation. The reduced damage and maintained ATP levels during anoxia may be due to the blockade of ion flux through the NMDA receptor ion channel. The decreased ion flux could act to reduce ATP utilization for ion pumping as well as reduce damage caused by altered cytosolic levels of certain ions (e.g., calcium).