Skip Navigation
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

National Institute of Environmental Health Sciences

Use this QR code to view the newest version of this document
Use this QR code to view the newest version of this document

Your Environment. Your Health.

Publication Detail

Title: Glutathione levels modulate domoic acid induced apoptosis in mouse cerebellar granule cells.

Authors: Giordano, Gennaro; White, Collin C; Mohar, Isaac; Kavanagh, Terrance J; Costa, Lucio G

Published In Toxicol Sci, (2007 Dec)

Abstract: Exposure of mouse cerebellar granule neurons (CGNs) to domoic acid induced cell death, either by apoptosis or by necrosis, depending on its concentration. Necrotic damage predominated in response to domoic acid above 0.1 microM. In contrast, cell injury with apoptotic features (assessed by Hoechst staining and DNA laddering assay) was evident after exposure to lower concentrations of domoic acid (< or = 0.1 microM). The AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid)/kainate receptor antagonist 2,3-dihydroxy-6-nitro-sulfamoylbenzo [f] quinoxaline, but not the N-methyl-D-aspartate receptor antagonist MK-801, prevented domoic acid-induced apoptosis. To evaluate the role of oxidative stress in domoic acid-induced apoptosis, experiments were carried out in CGNs isolated from wild-type mice (Gclm (+/+)) and mice lacking the modifier subunit of glutamate-cysteine ligase, the first and rate-limiting step of glutathione (GSH) biosynthesis (Gclm (-/-)). CGNs from Gclm (-/-) mice have very low levels of GSH and were more sensitive to domoic acid-induced apoptosis and necrosis than Gclm (+/+) CGNs. The antioxidant melatonin (200 microM) and the membrane-permeant GSH delivery agent GSH ethyl ester (2.5 mM) prevented domoic acid-induced apoptosis. Domoic acid increased formation of reactive oxygen species but did not affect intracellular GSH levels. Domoic acid also increased cytosolic and mitochondrial calcium levels, increased oxidative stress in mitochondria, and altered mitochondrial membrane potential, which ultimately caused cytochrome c release, activation of caspase-3, and degradation of poly (ADP-ribose) polymerase. These results indicate that low concentrations of domoic acid cause apoptotic neuronal cell death mediated by oxidative stress.

PubMed ID: 17804861 Exiting the NIEHS site

MeSH Terms: Animals; Antioxidants/pharmacology; Apoptosis/drug effects*; Cells, Cultured; Cerebellum/drug effects*; Cerebellum/pathology; Cytoplasmic Granules/drug effects; Cytoplasmic Granules/metabolism; Drug Antagonism; Enzymes/metabolism; Gene Silencing; Glutamate-Cysteine Ligase/deficiency; Glutamate-Cysteine Ligase/genetics; Glutathione/analogs & derivatives; Glutathione/metabolism*; Glutathione/pharmacology; Kainic Acid/analogs & derivatives*; Kainic Acid/toxicity; Melatonin/pharmacology; Membrane Potential, Mitochondrial/drug effects; Mice; Mice, Knockout; Mitochondria/drug effects; Mitochondria/metabolism; Neurons/drug effects*; Neurons/pathology; Neurotoxins/toxicity*; Reactive Oxygen Species

Back
to Top