title: Short-term hyperglycemia produces oxidative damage and apoptosis in neurons.
abstract: Dorsal root ganglia neurons in culture die through programmed cell death when exposed to elevated glucose, providing an in vitro model system for the investigation of the mechanisms leading to diabetic neuropathy. This study examines the time course of programmed cell death induction, regulation of cellular antioxidant capacity, and the protective effects of antioxidants in neurons exposed to hyperglycemia. We demonstrate that the first 2 h of hyperglycemia are sufficient to induce oxidative stress and programmed cell death. Using fluorimetric analysis of reactive oxygen species (ROS) production, in vitro assays of antioxidant enzymes, and immunocytochemical assays of cell death, we demonstrate superoxide formation, inhibition of aconitase, and lipid peroxidation within 1 h of hyperglycemia. These are followed by caspase-3 activation and DNA fragmentation. Antioxidant potential increases by 3-6 h but is insufficient to protect these neurons. Application of the antioxidant alpha-lipoic acid potently prevents glucose-induced oxidative stress and cell death. This study identifies cellular therapeutic targets to prevent diabetic neuropathy. Since oxidative stress is a common feature of the micro- and macrovascular complications of diabetes, the present findings have broad application to the treatment of diabetic patients.
authors.affiliation: University of Michigan, Department of Neurology, Ann Arbor, Michigan 48109, USA. andreav@umich.edu
authors.forename: Andrea M
authors.initials: AM
authors.lastname: Vincent
authors.forename: Lisa L
authors.initials: LL
authors.lastname: McLean
authors.forename: Carey
authors.initials: C
authors.lastname: Backus
authors.forename: Eva L
authors.initials: EL
authors.lastname: Feldman
mesh_terms: D000154:Aconitate Hydratase / Q000037:antagonists & inhibitors; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002374:Catalase / Q000378:metabolism; D002478:Cells, Cultured; D053938:DNA Fragmentation; D004789:Enzyme Activation; D005727:Ganglia, Spinal; D005947:Glucose / Q000494:pharmacology; D005978:Glutathione / Q000032:analysis; D006943:Hyperglycemia / Q000473:pathology* / Q000503:physiopathology*; D015227:Lipid Peroxidation; D009097:Multienzyme Complexes / Q000378:metabolism; D009247:NADH, NADPH Oxidoreductases / Q000378:metabolism; D009474:Neurons / Q000473:pathology* / Q000502:physiology*; D018384:Oxidative Stress / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D013482:Superoxide Dismutase / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism; D017392:Thiobarbituric Acid Reactive Substances / Q000032:analysis; D008063:Thioctic Acid / Q000494:pharmacology; D013997:Time Factors
chemical_list: D000975:Antioxidants; D009097:Multienzyme Complexes; D017392:Thiobarbituric Acid Reactive Substances; D013481:Superoxides; D008063:Thioctic Acid; D002374:Catalase; D013482:Superoxide Dismutase; C023107:NADH oxidase; D009247:NADH, NADPH Oxidoreductases; C505410:Casp3 protein, rat; D053148:Caspase 3; D020169:Caspases; D000154:Aconitate Hydratase; D005978:Glutathione; D005947:Glucose