ALTERATIONS OF BRAIN METABOLISM BY THE NEUROTOXIN, KAINIC ACID.
Item
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Title
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ALTERATIONS OF BRAIN METABOLISM BY THE NEUROTOXIN, KAINIC ACID.
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Identifier
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AAI8113484
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identifier
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8113484
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Creator
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KRESPAN, BARBARA.
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Contributor
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William J. Nicklas
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Date
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1981
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Language
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English
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Publisher
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City University of New York.
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Subject
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Health Sciences, Pharmacology
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Abstract
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A good correlation exists between the neurotoxic and neuroexcitatory properties of glutamic acid and several of its analogs, including kainic acid. Therefore it has been suggested that excitotoxic amino acids such as kainic acid generate in affected neurons a state of continuous depolarization and increase in membrane permeability which leads to neuronal cell death, possibly by depletion of high energy intermediates. In the present study, kainic acid (1 mM) caused a maximal 30-40% decrease in ATP levels of rat cerebellar slices which could be partially reversed by reincubation in drug-free medium. Creatine phosphate levels also decreased by 30-35% in the presence of 1 mM kainic acid. ADP and AMP levels were only slightly altered by 1 mM kainic acid, thus the total content of ATP + ADP + AMP decreased by 29%. Kainic acid was also found to decrease ATP levels of cerebellar slices from weaver mice which are genetic mutants lacking granule cells, the excitatory glutamergic interneurons of the cerebellum. This is in contrast to evidence suggesting that glutamergic neurons are necessary for kainic acid toxicity in the striatum.;The actions of kainic acid on glutamic acid metabolism in the cerebellar slice was studied. Kainic acid caused a decrease in tissue glutamine levels (60-70%), glutamic acid and aspartic acid levels (10-20%), and no alteration in GABA levels. Kainic acid caused a large decrease of the relative specific radioactivity (RSA) of glutamine from radioactive acetate and GABA, but not from radioactive glucose. This indicates that glutamine synthesis was inhibited in the "small" pool of glutamic acid metabolism, probably preferentially localized to glia. Kainic acid did not directly inhibit glutamine synthetase activity; the decrease in glutamine synthesis may result from a depletion of ATP at that site. These studies also confirmed previous observations that transferring of slices from preincubation to incubation medium is necessary to enhance phenomena interpreted as metabolic compartmentation. In contrast to cerebellar slices, kainic acid caused no alterations of ATP levels or of radioactive acetate incorporation into amino acids in striatal slices.;Kainic acid substantially increased the levels of glutamic acid (200-350%) and aspartic acid (220-250%) in the medium of cerebellar slices, but did not alter GABA or glutamine levels. This is consistent with the hypothesis that the release of excitatory substances is involved in the neurotoxic actions of kainic acid.;In control studies, a nonexcitatory glutamic acid uptake blocker, dihydrokainic acid (1 mM) did not alter ATP or amino acid levels. The neuroexcitant, DL-homocysteic acid (10 mM), but not N-methyl-DL-aspartic acid (1 mM), had similar effects as kainic acid.;The site from which kainic acid or veratridine released glutamic acid was compared. Veratridine, a presynaptic depolarizing agent, decreased the specific radioactivity of acetate-labelled glutamic acid in the medium by 38% and tended to increase (not significant) that of glucose-labelled glutamic acid by 16%. In addition, tetrodotoxin blocked the veratridine-induced efflux of glutamic acid, aspartic acid, and GABA. These data are consistent with veratridine causing release of presynaptic pools of glutamic acid. Kainic acid increased the specific radioactivity of glucose-labelled glutamic acid by 55% and tended to increase that of acetate-labelled glutamic acid by 43%. The release of glutamic acid and aspartic acid induced by kainic acid was not blocked by tetrodotoxin. Kainic acid also did not release glutamic acid from cortical synaptosomes. The data suggest that kainic acid released pools of glutamic acid from glia and neurons and these were different pools than veratridine released.
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Type
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dissertation
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Source
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PQT Legacy CUNY.xlsx
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degree
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Ph.D.
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Program
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Biomedical Sciences
