title: Oxidative stress in Niemann-Pick type C patients: a protective role of N-butyl-deoxynojirimycin therapy.
abstract: Niemann-Pick type C (NPC) is a rare neurodegenerative disorder biochemically characterized by the accumulation of cholesterol and glycosphingolipids in late endosomes and lysosomes of the affected patients. N-butyl-deoxynojirimycin is the only approved drug for patients with NPC disease. It inhibits glycosphingolipid synthesis, therefore reducing intracellular lipid storage. Although the mechanisms underlying the neurologic damage in the NPC disease are not yet well established, in vitro and in vivo studies suggest an involvement of reactive species in the pathophysiology of this disease. In this work we aimed to evaluate parameters of lipid and protein oxidation, measured by thiobarbituric acid-reactive species (TBA-RS) and protein carbonyl formation, respectively, as well as the enzymatic and non-enzymatic antioxidant defenses in plasma, erythrocytes and fibroblasts from NPC1 patients, at diagnosis and during treatment with N-butyl-deoxynojirimycin. We found a significant increase of TBA-RS in plasma and fibroblasts, as well as increased protein carbonyl formation and decreased total antioxidant status (TAS) in plasma of untreated NPC1 patients as compared to the control group. In addition, erythrocyte glutathione peroxidase (GSH-Px) activity was increased, whereas CAT and SOD activities were normal in these patients. We also observed that patients treated with N-butyl-deoxynojirimycin normalized plasma TBA-RS and TAS, as well as erythrocyte GSH-Px activity. Taken together, the present data indicate that oxidative stress is increased in patients with NPC1 disease and that treatment with N-butyl-deoxynojirimycin is able to confer protection against this pathological process.
authors: Programa de Pós-Graduação em Ciências Farmacêuticas, UFRGS, Ipiranga 2752, Porto Alegre, RS 90610-000, Brazil.
authors: Graziela S
authors: GS
authors: Ribas
authors: Ricardo
authors: R
authors: Pires
authors: Janice Carneiro
authors: JC
authors: Coelho
authors: Daiane
authors: D
authors: Rodrigues
authors: Caroline Paula
authors: CP
authors: Mescka
authors: Camila S
authors: CS
authors: Vanzin
authors: Giovana B
authors: GB
authors: Biancini
authors: Giovanna
authors: G
authors: Negretto
authors: Carlos A Y
authors: CA
authors: Wayhs
authors: Moacir
authors: M
authors: Wajner
authors: Carmen R
authors: CR
authors: Vargas
mesh_terms: D017485:1-Deoxynojirimycin / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D000293:Adolescent; D000328:Adult; D000975:Antioxidants / Q000378:metabolism; D002374:Catalase / Q000378:metabolism; D002648:Child; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D004912:Erythrocytes / Q000187:drug effects; D005260:Female; D005347:Fibroblasts / Q000187:drug effects; D005978:Glutathione / Q000378:metabolism; D005979:Glutathione Peroxidase / Q000378:metabolism; D006801:Humans; D007223:Infant; D008137:Longitudinal Studies; D008297:Male; D052556:Niemann-Pick Disease, Type C / Q000097:blood / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology*; D018384:Oxidative Stress / Q000187:drug effects* / Q000502:physiology*; D010949:Plasma / Q000187:drug effects; D050050:Protein Carbonylation / Q000187:drug effects; D018709:Statistics, Nonparametric; D013482:Superoxide Dismutase / Q000378:metabolism; D017392:Thiobarbituric Acid Reactive Substances / Q000378:metabolism; D055815:Young Adult
chemical_list: D000975:Antioxidants; D004791:Enzyme Inhibitors; D017392:Thiobarbituric Acid Reactive Substances; D017485:1-Deoxynojirimycin; C059896:miglustat; D002374:Catalase; D005979:Glutathione Peroxidase; D013482:Superoxide Dismutase; D005978:Glutathione