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Research ArticleArticle

Neurotoxicity of Domoic Acid in Cerebellar Granule Neurons in a Genetic Model of Glutathione Deficiency

G. Giordano, C. C. White, L. A. McConnachie, C. Fernandez, T. J. Kavanagh and L. G. Costa
Molecular Pharmacology December 2006, 70 (6) 2116-2126; DOI: https://doi.org/10.1124/mol.106.027748
G. Giordano
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C. C. White
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L. A. McConnachie
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C. Fernandez
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T. J. Kavanagh
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L. G. Costa
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Abstract

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 α-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.

Footnotes

  • This study was supported by National Institutes of Health grants ES012762/NSF-OCE-0434087, R01-ES10849, P42-ES04696, T32-ES007032, and P30-ES07033.

  • ABBREVIATIONS: DomA, domoic acid; KA, kainic acid; AMPA, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid; ROS, reactive oxygen species; GSH, glutathione; GSHEE, glutathione ethylester; GCLM, glutamate-cysteine ligase modifier subunit; GCLC, glutamate-cysteine ligase catalytic subunit; MK-801, 5H-dibenzo[a,d]cyclohepten-5,10-imine (dizocilpine maleate); SOD, superoxide dismutase; BSO, l-buthionine-(S,R)-sulfoximine; BHT, butylated hydroxytoluene; PBN, N-t-butyl-α-phenylnitrone; DMSO, dimethyl sulfoxide; MTT, 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide; MBB, monobromobimane; NMDA, N-methyl-d-aspartate; CNQX, 6-cyano-7-nitroquinoxaline-2,3-dione disodium; NBQX, 2,3-dihydroxy-6-nitro-sulfamoylbenzo (f)quinoxaline; TCEP, tris(2-carboxyethyl)-phosphine hydrochloride; ES, embryonic stem; CGN, cerebellar granule neuron; FBS, fetal bovine serum; SSA, 5-sulfosalicylic acid; GSSG, glutathione disulfide; HPLC, high-performance liquid chromatography; BAPTA-AM, 1,2-bis(2-amino-5-methylphenoxy)ethane-N,N,N′,N′-tetraacetic acid tetrakis(acetoxymethyl) ester; DCFH2-DA, 2,7′-dichlorofluorescein diacetate; DCF, 2,7′-dichlorofluorescein; AM, acetoxymethyl ester; MDA, malondialdehyde; γ-GT, γ-glutamyltranspeptidase.

    • Received June 8, 2006.
    • Accepted September 25, 2006.
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 70 (6)
Molecular Pharmacology
Vol. 70, Issue 6
1 Dec 2006
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Research ArticleArticle

Neurotoxicity of Domoic Acid in Cerebellar Granule Neurons in a Genetic Model of Glutathione Deficiency

G. Giordano, C. C. White, L. A. McConnachie, C. Fernandez, T. J. Kavanagh and L. G. Costa
Molecular Pharmacology December 1, 2006, 70 (6) 2116-2126; DOI: https://doi.org/10.1124/mol.106.027748

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Research ArticleArticle

Neurotoxicity of Domoic Acid in Cerebellar Granule Neurons in a Genetic Model of Glutathione Deficiency

G. Giordano, C. C. White, L. A. McConnachie, C. Fernandez, T. J. Kavanagh and L. G. Costa
Molecular Pharmacology December 1, 2006, 70 (6) 2116-2126; DOI: https://doi.org/10.1124/mol.106.027748
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