Protective Effect of the Xanthate, D609, on Alzheimer's Amyloid β-peptide (1–42)-induced Oxidative Stress in Primary Neuronal Cells

Abstract

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 beta-peptide [Abeta(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 Abeta(1-42)-induced oxidative cell toxicity in cultured neurons. Decreased cell survival in neuronal cultures treated with Abeta(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 Abeta(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 Abeta(1-42)-induced oxidative stress. Our results suggest that D609 exerts protective effects against Abeta(1-42) toxicity by modulating oxidative stress. These results may be of importance for the treatment of AD and other oxidative stress-related diseases.

In vivo administration of D609 leads to protection of subsequently isolated gerbil brain mitochondria subjected to in vitro oxidative stress induced by amyloid beta-peptide and other oxidative stressors: Relevance to Alzheimer’s disease and other oxidative stress-related neurodegenerative disorders

“…Recently, we showed that the xanthate D609, a glutathione mimetic [44], protects primary neuronal culture against Aβ (1-42)-induced oxidative stress and neurotoxicity in vitro [45] and against Aβ (1-42) in vivo [46]. D609 has the ability to scavenge hydrogen peroxide and hydroxyl free radicals [44].…”

“…Such inhibition decreases production of the secondary messenger diacylglycerol (DAG) that activates protein kinase C (PKC) and acidic sphingomyelinase (aSMase) [40]. However, with a free thiol group, D609 may also possess strong antioxidant activity [41] with in vitro and in vivo radical scavenging properties and inhibition of free radialinduced oxidative stress [42][43][44][45][46].…”

“…The particular species of ROS that D609 can effectively scavenge is not clear, but this xanthate has ability to scavenge hydroxyl radicals [42][43][44][45][46]. The reaction with other ROS is also possible since xanthates generally have high reductive potential [41].…”

Oxidative stress and toxicity induced by the nucleoside reverse transcriptase inhibitor (NRTI)—2′,3′-dideoxycytidine (ddC): Relevance to HIV-dementia

“…We report here that ddC, at concentrations achievable in the CSF, induces oxidative stress when added to synaptosomes and isolated mitochondria. The levels of oxidative stress as measured by protein carbonyls on synaptosomes were significantly reduced upon the use of a known brain accessible antioxidant and glutathione mimetic [D609] (Zhou et al 2001;Lauderback et al 2003;Sultana et al 2004). In addition, we observed a significant reduction in the levels of the anti-apoptotic protein Bcl-2, a significant release of cytochrome c and an equally significant increase in caspase-3 protein levels upon treatment of mitochondria with ddC, suggesting the induction of apoptotic process following treatment with ddC.…”

Aluminum inhibits proteolytic degradation of amyloid β peptide by cathepsin D: A potential link between aluminum accumulation and neuritic plaque deposition

“…Interestingly, recent studies clearly suggest that neurotoxicity exerted by senile plaques arises from the induction of oxidative stress [49][50][51]. Furthermore, Pratico et al [52] reported that Al increased in vivo lipid peroxidation, as well as Al-accelerated Ab peptide formation and plaque deposition in amyloid precursor protein transgenic mice.…”