Neurotoxicity of methylglyoxal and 3-deoxyglucosone on cultured cortical neurons: synergism between glycation and oxidative stress, possibly involved in neurodegenerative diseases.
In this study, we investigate the neurotoxicity of glycation, particularly early-stage glycation, and its mechanisms, which are possibly synergized with oxidative stress. Methylglyoxal (MG) and 3-deoxyglucosone (3DG), intermediate products of glycation, are known to further accelerate glycation and advanced glycation endproducts (AGEs) formation. Both compounds showed neurotoxicity on cultured cortical neurons and these effects were associated with reactive oxygen species production followed by neuronal apoptosis. Pretreatment with N-acetylcysteine induced neuroprotection against MG and 3DG. Cotreatment, but not pretreatment, with aminoguanidine protected neurons against the neurotoxicities of both compounds. The present study provides the first evidence that MG and 3DG are neurotoxic to cortical neurons in culture. Interference with the process by which glycation and AGEs formation occur may provide new therapeutic opportunities to reduce the pathophysiological changes associated with neurodegeneration, if, as indicated here, the participation of glycoxidation in the pathogenesis of neurodegenerative diseases is essential.
Department of Neurology, Hokkaido University School of Medicine, Sapporo, Hokkaido, Japan. skikuti@med.hokudai.ac.jp
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Kikuchi
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Shinpo
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Moriwaka
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Makita
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Miyata
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Tashiro
D000111:Acetylcysteine / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D003847:Deoxyglucose / Q000031:analogs & derivatives* / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D016166:Free Radical Scavengers / Q000494:pharmacology; D017127:Glycation End Products, Advanced / Q000032:analysis / Q000378:metabolism; D006031:Glycosylation; D019636:Neurodegenerative Diseases / Q000378:metabolism*; D009474:Neurons / Q000737:chemistry / Q000166:cytology* / Q000378:metabolism; D018384:Oxidative Stress / Q000502:physiology*; D010545:Peroxides / Q000378:metabolism; D011765:Pyruvaldehyde / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley
D016166:Free Radical Scavengers; D017127:Glycation End Products, Advanced; D010545:Peroxides; D011765:Pyruvaldehyde; D003847:Deoxyglucose; C016350:3-deoxyglucosone; D000111:Acetylcysteine