Protective effect of the xanthate, D609, on Alzheimer's amyloid β-peptide (1-42)-induced oxidative stress in primary neuronal cells

Rukhsana Sultana, Shelley Newman, Hafiz Mohmmad-Abdul, Jeffery N. Keller, D. Allan Butterfield

Research output: Contribution to journalArticlepeer-review

86 Scopus citations


Tricyclodecan-9-yl-xanthogenate (D609) is an inhibitor of phosphatidylcholine-specific phospholipase C, and this agent also has been reported to protect rodents against oxidative damage induced by ionizing radiation. Previously, we showed that D609 mimics glutathione (GSH) functions and that a disulfide is formed upon oxidation of D609 and the resulting dixanthate is a substrate for GSH reductase, regenerating D609. Considerable attention has been focused on increasing the intracellular GSH levels in many diseases, including Alzheimer's disease (AD). Amyloid β-peptide [Aβ(1-42)], elevated in AD brain, is associated with oxidative stress and toxicity. The present study aimed to investigate the protective effects of D609 on Aβ(1-42)-induced oxidative cell toxicity in cultured neurons. Decreased cell survival in neuronal cultures treated with Aβ(1-42) correlated with increased free radical production measured by dichlorofluorescein fluorescence and an increase in protein oxidation (protein carbonyl, 3-nitrotyrosine) and lipid peroxidation (4-hydroxy-2-nonenal) formation. Pretreatment of primary hippocampal cultures with D609 significantly attenuated Aβ (1-42)-induced cytotoxicity, intracellular ROS accumulation, protein oxidation, lipid peroxidation and apoptosis. Methylated D609, with the thiol functionality no longer able to form the disulfide upon oxidation, did not protect neuronal cells against Aβ(1-42)-induced oxidative stress. Our results suggest that D609 exerts protective effects against Aβ(1-42) toxicity by modulating oxidative stress. These results may be of importance for the treatment of AD and other oxidative stress-related diseases.

Original languageEnglish
Pages (from-to)449-458
Number of pages10
JournalFree Radical Research
Issue number5
StatePublished - May 2004

Bibliographical note

Funding Information:
This research was supported in part by grants from NIH [AG-10836; AG-05119].


  • Aβ(1-42)
  • Cortical neurons
  • Glutathione
  • Lipid peroxidation
  • Protein carbonyl
  • Tricyclodecan-9-yl-xanthogenate

ASJC Scopus subject areas

  • Biochemistry


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