PT  - JOURNAL ARTICLE
AU  - Zeevalk, G D
AU  - Nicklas, W J
TI  - Mechanisms underlying initiation of excitotoxicity associated with metabolic inhibition.
DP  - 1991 May 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 870--878
VI  - 257
IP  - 2
4099  - http://jpet.aspetjournals.org/content/257/2/870.short
4100  - http://jpet.aspetjournals.org/content/257/2/870.full
SO  - J Pharmacol Exp Ther1991 May 01; 257
AB  - "Graded" metabolic stress was induced chemically in an ex vivo preparation of retina to examine the early events following metabolic inhibition that lead to acute toxicity. Toxicity was assessed histologically and by quantitation of endogenous gamma-aminobutyric acid (GABA) release. Blockade of glycolysis with iodoacetate or electron transport with potassium cyanide for 30 min ("mild" metabolic stress) produced histopathology and GABA release similar to that seen with glutamate agonist treatment. These effects were completely prevented by the N-methyl-D-aspartate (NMDA) antagonist [(+)-5-methyl-10,11-dihydro-5H-dibenzo (a,d)cyclohepten,5,10-imine maleate (MK-801) and occurred in the absence of any net increase in extracellular glutamate or aspartate. More "severe" compromise of metabolism (iodoacetate plus potassium cyanide for 30 min) caused greater swelling and GABA release, which was only partially attenuated by competitive or noncompetitive NMDA antagonists and was accompanied by elevations in extracellular excitatory amino acids. Temporal studies of "severe" metabolic inhibition and the rise in excitatory amino acids demonstrated that, like "mild" metabolic inhibition, the early acute pathology was mediated exclusively by the NMDA receptor and occurred before elevation in excitatory amino acids. Tetrodotoxin and 6-nitro,7-cyanoquinoxaline,2,3-dion (CNQX) had little effect per se on reducing GABA release under conditions of "severe" metabolic inhibition; however, CNQX or tetrodotoxin in combination with MK-801 afforded greater protection than did MK-801 alone. Thus, activity at kainate/AMPA receptors and voltage-sensitive Na+ channels may be additional factors contributing to acute toxicity.(ABSTRACT TRUNCATED AT 250 WORDS)