Neurotoxicity of domoic Acid in cerebellar granule neurons in a genetic model of glutathione deficiency.

Neurotoxicity of domoic Acid in cerebellar granule neurons in a genetic model of glutathione deficiency. Research Abstract Details 

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Neurotoxicity of domoic Acid in cerebellar granule neurons in a genetic model of glutathione deficiency. Abstract Text:

G Giordano,C C White,L A McConnachie,C Fernandez,T J Kavanagh,L G Costa,

This study investigated the role of cellular antioxidant defense mechanisms in modulating the neurotoxicity of domoic acid (DomA), by using cerebellar granule neurons (CGNs) from mice lacking the modifier subunit of glutamate-cysteine ligase (Gclm). Glutamate-cysteine ligase (Glc) catalyzes the first and rate-limiting step in glutathione (GSH) biosynthesis. CGNs from Gclm (-/-) mice have very low levels of GSH and are 10-fold more sensitive to DomA-induced toxicity than CGNs from Gclm (+/+) mice. GSH ethyl ester decreased, whereas the Gcl inhibitor buthionine sulfoximine increased DomA toxicity. Antagonists of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid/kainate receptors and of N-methyl-D-aspartate (NMDA) receptors blocked DomA toxicity, and NMDA receptors were activated by DomA-induced l-glutamate release. The differential susceptibility of CGNs to DomA toxicity was not due to a differential expression of ionotropic glutamate receptors, as evidenced by similar calcium responses and L-glutamate release in the two genotypes. A calcium chelator and several antioxidants antagonized DomA-induced toxicity. DomA caused a rapid decrease in cellular GSH, which preceded toxicity, and the decrease was primarily due to DomA-induced GSH efflux. DomA also caused an increase in oxidative stress as indicated by increases in reactive oxygen species and lipid peroxidation, which was subsequent to GSH efflux. Astrocytes from both genotypes were resistant to DomA toxicity and presented a diminished calcium response to DomA and a lack of DomA-induced L-glutamate release. Because polymorphisms in the GCLM gene in humans are associated with low GSH levels, such individuals, as well as others with genetic conditions or environmental exposures that lead to GSH deficiency, may be more susceptible to DomA-induced neurotoxicity.

Neurotoxicity of domoic Acid in cerebellar granule neurons in a genetic model of glutathione deficiency. Publishing Authors By Initials

G Giordano,CC White,LA McConnachie,C Fernandez,TJ Kavanagh,LG Costa,

For similar nervous system: neurons research abstracts see: nervous system: neurons research

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MEDLINE DATE:

Neurotoxicity of domoic Acid in cerebellar granule neurons in a genetic model of glutathione deficiency. Journal Published:

PUBLICATION TYPE: Research Support, U.S. Gov't,

Journal: Molecular pharmacology

VOLUME: 70

Page Numbers: 2116-26

Journal Abbreviation: Mol. Pharmacol.

ISSN: 0026-895X

DAY: 25

MONTH: 09

YEAR: 2006

Neurotoxicity of domoic Acid in cerebellar granule neurons in a genetic model of glutathione deficiency. Information

Number of References:

LANGUAGE: eng

NlmUniqueID: 35623

Neurotoxicity of domoic Acid in cerebellar granule neurons in a genetic model of glutathione deficiency. Keywords Mesh Terms:

KEYWORDS: Neurons

MESH TERMS: metabolism

Chemical & Substance for Abstract: Neurotoxicity of domoic Acid in cerebellar granule neurons in a genetic model of glutathione deficiency. Information

Substance Name: Glutathione

Registry Number: 70-18-8

Grant and Affiliation Information for Neurotoxicity of domoic Acid in cerebellar granule neurons in a genetic model of glutathione deficiency.

AFFILIATION: Department of Environmental and Occupational Health Sciences, University of Washington, 4225 Roosevelt Way NE, Suite 100, Seattle, WA 98105, USA.

Country: United States

AGENCY: United States NIEHS

GRANT: T32-ES007032

ACRONYM: ES

MEDLINETA: Mol Pharmacol

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