In vivo protection by the xanthate tricyclodecan-9-yl-xanthogenate against amyloid beta-peptide (1-42)-induced oxidative stress.
Considerable evidence supports the role of oxidative stress in the pathogenesis of Alzheimer's disease. One hallmark of Alzheimer's disease is the accumulation of amyloid beta-peptide, which invokes a cascade of oxidative damage to neurons that can eventually result in neuronal death. Amyloid beta-peptide is the main component of senile plaques and generates free radicals ultimately leading to neuronal damage of membrane lipids, proteins and nucleic acids. Therefore, interest in the protective role of different antioxidant compounds has been growing for treatment of Alzheimer's disease and other oxidative stress-related disorders. Among different antioxidant drugs, much interest has been devoted to "thiol-delivering" compounds. Tricyclodecan-9-yl-xanthogenate is an inhibitor of phosphatidylcholine specific phospholipase C, and recent studies reported its ability to act as a glutathione-mimetic compound. In the present study, we investigate the in vivo ability of tricyclodecan-9-yl-xanthogenate to protect synaptosomes against amyloid beta-peptide-induced oxidative stress. Gerbils were injected i.p. with tricyclodecan-9-yl-xanthogenate or with saline solution, and synaptosomes were isolated from the brain. Synaptosomal preparations isolated from tricyclodecan-9-yl-xanthogenate injected gerbils and treated ex vivo with amyloid beta-peptide (1-42) showed a significant decrease of oxidative stress parameters: reactive oxygen species levels, protein oxidation (protein carbonyl and 3-nitrotyrosine levels) and lipid peroxidation (4-hydroxy-2-nonenal levels). Our results are consistent with the hypothesis that modulation of free radicals generated by amyloid beta-peptide might represent an efficient therapeutic strategy for treatment of Alzheimer's disease and other oxidative-stress related disorders. Based on the above data, we suggest that tricyclodecan-9-yl-xanthogenate is a potent antioxidant and could be of importance for the treatment of Alzheimer's disease and other oxidative stress-related disorders.
Perluigi
M
M
Department of Biochemical Sciences, University of Rome La Sapienza, Rome 00185, Italy.
Joshi
G
G
Sultana
R
R
Calabrese
V
V
De Marco
C
C
Coccia
R
R
Butterfield
D A
DA
D000447:Aldehydes / Q000037:antagonists & inhibitors / Q000378:metabolism; D000544:Alzheimer Disease / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors* / Q000633:toxicity; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology / Q000627:therapeutic use; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D001952:Bridged-Ring Compounds / Q000494:pharmacology* / Q000627:therapeutic use; D004195:Disease Models, Animal; D005609:Free Radicals / Q000037:antagonists & inhibitors / Q000378:metabolism; D005849:Gerbillinae; D015227:Lipid Peroxidation / Q000187:drug effects / Q000502:physiology; D008297:Male; D009410:Nerve Degeneration / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D009636:Norbornanes; D018384:Oxidative Stress / Q000187:drug effects* / Q000502:physiology; D010446:Peptide Fragments / Q000037:antagonists & inhibitors* / Q000633:toxicity; D017382:Reactive Oxygen Species / Q000037:antagonists & inhibitors / Q000378:metabolism; D013574:Synaptosomes; D013859:Thiocarbamates; D013871:Thiones / Q000494:pharmacology* / Q000627:therapeutic use; D010738:Type C Phospholipases / Q000037:antagonists & inhibitors / Q000378:metabolism; D014443:Tyrosine / Q000031:analogs & derivatives / Q000037:antagonists & inhibitors / Q000378:metabolism
D000447:Aldehydes; D016229:Amyloid beta-Peptides; D000975:Antioxidants; D001952:Bridged-Ring Compounds; D005609:Free Radicals; D009636:Norbornanes; D010446:Peptide Fragments; D017382:Reactive Oxygen Species; D013859:Thiocarbamates; D013871:Thiones; C075222:amyloid beta-protein (1-42); C002744:3-nitrotyrosine; D014443:Tyrosine; C046498:tricyclodecane-9-yl-xanthogenate; D010738:Type C Phospholipases; C027576:4-hydroxy-2-nonenal