Derivatives of Xanthic Acid are Novel Antioxidants: Application to Synaptosomes

Abstract

Xanthic acids have long been known to act as reducing agents. Recently, D609, a tricyclodecanol derivative of xanthic acid, has been reported to have anti-apoptotic and anti-inflammatory properties that are attributed to specific inhibition of phosphatidyl choline phospholipase C (PC-PLC). However, because oxidative stress is involved in both of these cellular responses, the possibility that xanthates may act as antioxidants was investigated in the current study. Finding that xanthates efficiently scavenge hydroxyl radicals, the mechanism by which D609 and other xanthate derivatives may protect against oxidative damage was further examined. The xanthates studied, especially D609, mimic glutathione (GSH). Xanthates scavenge hydroxyl radicals and hydrogen peroxide, form disulfide bonds (dixanthogens), and react with electrophilic products of lipid oxidation (acrolein) in a manner similar to GSH. Further, upon disulfide formation, dixanthogens are reduced by glutathione reductase to a redox active xanthate. Supporting its role as an antioxidant, D609 significantly (p < 0.01) reduces free radical-induced changes in synaptosomal lipid peroxidation (TBARs), protein oxidation (protein carbonyls), and protein conformation. Thus, in addition to inhibitory effects on PC-PLC, D609 may prevent cellular apoptotic and inflammatory cascades by acting as antioxidants and novel GSH mimics. These results are discussed with reference to potential therapeutic application of D609 in oxidative stress conditions.

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

“…GSH can also protect brain from damage by peroxynitrite, hydroxyl free radicals, or reactive alkenals [63][64][65][66]75]. D609 may binds to reactive alkenals formed due to peroxidation of lipids and detoxifies their effects [44].…”

“…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].…”

“…D609 may protect intracellular GSH, which is important intracellular defense molecule against oxidative stress in neurons and has been shown to play an important role in radiation protection [43,47,48]. Recently, we showed that D609, a glutathione mimetic [44], protects primary neuronal culture against amyloid β-peptide [Aβ (1-42)]-induced oxidative stress and neurotoxicity in vitro [49] and in synaptosomes in vivo [46].…”