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Mechanisms underlying initiation of excitotoxicity associated with metabolic inhibition
1Department of Neurology, UMDNJ-Robert Wood Johnson Medical School, Piscataway.
Abstract:
"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)
Insights
Metabolic stress in retinas causes toxicity, with early events mediated by N-methyl-D-aspartate (NMDA) receptors. Severe stress also involves other receptors and channels, indicating complex pathways in retinal damage.
Area of Science:
- Neuroscience
- Ophthalmology
- Toxicology
Background:
- Metabolic inhibition is a known cause of cellular damage.
- Understanding early events in retinal toxicity is crucial for developing treatments.
Purpose of the Study:
- To investigate the early mechanisms of acute retinal toxicity induced by graded metabolic stress.
- To determine the role of specific receptors and ion channels in this process.
Main Methods:
- Ex vivo retinal preparation subjected to chemical induction of metabolic stress (iodoacetate and/or potassium cyanide).
- Histological assessment of tissue damage.
- Quantification of endogenous gamma-aminobutyric acid (GABA) release.
- Pharmacological manipulation using NMDA antagonists (MK-801), AMPA/kainate antagonists (CNQX), and sodium channel blockers (tetrodotoxin).
Main Results:
- Mild metabolic stress induced histopathology and GABA release, preventable by NMDA receptor blockade (MK-801).
- Severe metabolic stress caused greater damage and GABA release, only partially attenuated by NMDA antagonists, and was associated with elevated excitatory amino acids.
- Early acute pathology in both mild and severe stress was NMDA receptor-dependent and preceded excitatory amino acid increases.
- Combined blockade of NMDA receptors, AMPA/kainate receptors, and sodium channels provided greater protection than NMDA blockade alone.
Conclusions:
- Early retinal toxicity from metabolic inhibition is primarily mediated by NMDA receptor activation.
- Severe metabolic stress involves additional pathways, including kainate/AMPA receptors and voltage-sensitive sodium channels, contributing to acute toxicity.
- Targeting multiple pathways may offer enhanced neuroprotection against metabolic insults in the retina.