Kainate toxicity in energy-compromised rat hippocampal slices: differences between oxygen and glucose deprivation

Abstract

The effects of kainate (KA) on the recovery of neuronal function in rat hippocampal slices after hypoxia or glucose deprivation (GD) were investigated and compared to those of ( R,S)-α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA). KA and AMPA were found to be more toxic than either N-methyl- d-aspartate (NMDA), quinolinate, or glutamate, both under normal conditions and under states of energy deprivation. Doses as low as 1 μM KA or AMPA were sufficient to significantly reduce the recovery rate of neuronal function in slices after a standardized period of hypoxia or GD. The enhancement of hypoxic neuronal damage by both agonists could be partially blocked by the antagonist kynurenate, by the NMDA competitive antagonist AP5, and by elevating [Mg 2+] in or by omitting Ca 2+ from the perfusion medium. The AMPA antagonist glutamic acid diethyl ester was ineffective in preventing the enhanced hypoxic neuronal damage by either KA or AMPA. The antagonist of the glycine modulatory site on the NMDA receptor, 7-chlorokynurenate, did not block the KA toxicity but was able to block the toxicity of AMPA. 2,3-Dihydroxyquinoxaline completely blocked the KA- and AMPA-enhanced hypoxic neuronal damage. The KA-enhanced, GD-induced neuronal damage was prevented by Ca 2+ depletion and partially antagonized by kynurenate but not by AP5 or elevated [Mg 2+]. The results of the present study indicate that the KA receptor is involved in the mechanism of neuronal damage induced by hypoxia and GD, probably allowing Ca 2+ influx and subsequent intracellular Ca 2+ overload. In hypoxia, KA and AMPA appear to activate both their own receptors and the NMDA receptor; under GD conditions, KA mainly activates its own receptor.