Hypothermia, metabolic stress, and NMDA-mediated excitotoxicity.
Isolated embryonic retinas were metabolically stressed by inhibition of glycolysis either with iodoacetate (IOA) or by glucose withdrawal plus 10 mM 2-deoxy-D-glucose, and the effects of hypothermia were examined. Incubation at 30 versus 37 degrees C during 30 min of hypoglycemia with IOA completely reduced the rapid swelling-related GABA release [6 +/- 2 vs. 68 +/- 10 nmol/100 mg of protein (mean +/- SEM) for 30 and 37 degrees C, respectively]. Histology of the retina immediately following 30 min of metabolic stress at 30 degrees C appeared normal, whereas that at 37 degrees C showed a pattern of acute edema, characteristic of NMDA-mediated acute excitotoxicity. Coincubation with a competitive or noncompetitive NMDA antagonist, respectively, CGS-19755 (10 microM) or MK-801 (1 microM), during 30 min of hypoglycemia at 37 degrees C completely prevented tissue swelling, whereas extracellular GABA content remained at basal levels, indicating that the cytotoxic effects of IOA treatment for 30 min at 37 degrees C were NMDA receptor mediated. Longer periods of hypoglycemia at 37 degrees C produced acute toxicity that was only partially NMDA receptor mediated. Hypothermia delayed the onset of NMDA-mediated toxicity by 30-60 min. At 30 degrees C, the rate of loss of ATP was slowed during the first several minutes of hypoglycemia (82 and 58% of maximal tissue levels at 30 and 37 degrees C, respectively, at 5 min, but by 10 min, ATP levels were comparably reduced. After a transient exposure of retina to 50 microM NMDA in Mg(2+)-free medium, hypothermia significantly attenuated acute GABA release by 30%.(ABSTRACT TRUNCATED AT 250 WORDS)
University of Medicine and Dentistry-Robert Wood Johnson Medical School, Piscataway, New Jersey 08854.
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D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D002642:Chick Embryo; D006019:Glycolysis; D007003:Hypoglycemia / Q000378:metabolism* / Q000473:pathology*; D007036:Hypothermia, Induced; D016202:N-Methylaspartate / Q000502:physiology*; D009498:Neurotoxins / Q000378:metabolism*; D012160:Retina / Q000378:metabolism / Q000473:pathology; D013997:Time Factors
D009498:Neurotoxins; D016202:N-Methylaspartate; D000255:Adenosine Triphosphate