Chemically induced hypoglycemia and anoxia: relationship to glutamate receptor-mediated toxicity in retina.

Abstract

Chemically induced hypoglycemia and anoxia were evaluated in embryonic day 13 chicken retina to determine if excitotoxicity was a consequence of these conditions and if this was preceded by the net release of glutamate or aspartate. Retina incubated with iodoacetate (IOA), to inhibit glycolysis, or potassium cyanide (KCN), to inhibit electron transport, produced histological lesions similar to those found with N-methyl-D-aspartate (NMDA) or kainate. An increase in gamma-aminobutyric acid release, which has been used previously as a marker of excitatory amino acid-induced acute excitotoxicity, was also found to occur with IOA or KCN treatment. The NMDA antagonists 2-amino-5-phosphonovalerate and MK-801 [(+)-11-dihydro-5H-dibenzo[a,d]cyclohepten,5,10-imine maleate] protected retina from IOA- or KCN-induced lesioning and prevented the increase in gamma-aminobutyric acid release. The non-NMDA glutamate antagonist, 6-nitro,7-cyano-quinoxaline,2,3-dion, had little effect suggesting that the damage was mediated predominantly by the NMDA receptor. Extracellular glutamate and aspartate concentrations remained low (less than 0.2 microM) throughout incubation. Thus, the data furnish no evidence that an increase in released glutamate or aspartate is responsible for the activation of the NMDA receptor. Lactate production, ATP and phosphocreatine concentrations were also measured. ATP and phosphocreatine, but not lactate, levels were correlated with the induction of an acute excitotoxic lesion. The depletion of high energy phosphates and the first appearance of acute excitotoxicity were temporally distinct. Possible mechanisms linking metabolic inhibition and NMDA receptor-mediated acute excitotoxicity are discussed.