Protective effect of the xanthate, D609, on Alzheimer's amyloid beta-peptide (1-42)-induced oxidative stress in primary neuronal cells.
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.
Department of Chemistry, University of Kentucky, Lexington, KY 40506, USA.
Rukhsana
R
Sultana
Shelley
S
Newman
Hafiz
H
Mohmmad-Abdul
Jeffery N
JN
Keller
D Allan
DA
Butterfield
D000544:Alzheimer Disease / Q000188:drug therapy* / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000633:toxicity*; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D001952:Bridged-Ring Compounds / Q000627:therapeutic use*; D002478:Cells, Cultured; D005452:Fluoresceins; D005453:Fluorescence; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D015227:Lipid Peroxidation; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D009636:Norbornanes; D018384:Oxidative Stress / Q000187:drug effects*; D010446:Peptide Fragments / Q000633:toxicity*; D020011:Protective Agents; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D013859:Thiocarbamates; D013871:Thiones / Q000627:therapeutic use*; D010738:Type C Phospholipases / Q000037:antagonists & inhibitors
D016229:Amyloid beta-Peptides; D000970:Antineoplastic Agents; D001952:Bridged-Ring Compounds; D005452:Fluoresceins; D009636:Norbornanes; D010446:Peptide Fragments; D020011:Protective Agents; D017382:Reactive Oxygen Species; D013859:Thiocarbamates; D013871:Thiones; C075222:amyloid beta-protein (1-42); C046498:tricyclodecane-9-yl-xanthogenate; D010738:Type C Phospholipases