D609 (tricyclodecan-9-yl-xanthogenate) is a phosphatidylcholine-specific phospholipase C inhibitor that also has been reported to protect rodents against oxidative damage caused by lethal doses of ionizing radiation. We previously showed that D609 mimics glutathione. D609 has a free thiol group, which upon oxidation forms a disulfide. The resulting dixanthate is a substrate for glutathione reductase, regenerating D609. Recent studies from our laboratory have also shown that D609 reduces the Alzheimer amyloid beta-peptide (1-42)-induced oxidative stress and cytotoxicity in neuronal cell culture. The present study was undertaken to test the hypothesis that D609 would provide neuroprotection against free radical oxidative stress in vivo. Synaptosomes isolated from gerbils, previously injected intraperitoneally (ip) with D609, were treated with the oxidants Fe2+/H2O2 or 2,2-azobis-(2-amidinopropane) dihydrochloride (AAPH), which produce free radicals. Synaptosomes isolated from the gerbils ip injected with D609 and treated with Fe2+/H2O2 or AAPH showed significant reduction in reactive oxygen species, levels of protein carbonyl, protein-bound hydroxynonenal (a lipid peroxidation product), and 3-nitrotyrosine (another marker of protein oxidation formed by reaction of tyrosine residues with peroxynitrite) compared to oxidative stress in synaptosomes isolated from gerbils that were injected with saline, but treated with Fe2+/H2O2 or AAPH. These results are discussed with reference to the potential use of this brain-accessible glutathione mimetic in the treatment of oxidative stress-related neurodegenerative disorders.