title: Induction of oxidative stress by chronic and acute glutaric acid administration to rats.
abstract: : 1. Glutaric acidemia type I (GA I) is a neurometabolic disorder caused by deficiency of glutaryl-CoA dehydrogenase, which leads to tissue accumulation of predominantly glutaric acid (GA) and also 3-hydroxyglutaric acid to a lesser amount. Affected patients usually present progressive cortical atrophy and acute striatal degeneration attributed to the toxic accumulating metabolites.2. In the present study, we determined a number of oxidative stress parameters, namely chemiluminescence, thiobarbituric acid-reactive substances (TBA-RS), total antioxidant reactivity (TAR), glutathione (GSH) levels, and the activities of catalase and glutathione peroxidase (GPx), in various tissues from rats chronically exposed to GA or to saline (controls). High GA concentrations, similar to those found in glutaric aciduria type I, were induced in the brain by three daily subcutaneous injections of saline-buffered GA (5 micromol/g body weight) to Wistar rats of 5-22 days of life. The parameters were assessed 12 h after the last GA administration in different brain structures, skeletal muscle, heart, liver, erythrocytes, and plasma. The lipid peroxidation parameters chemiluminescence and/or TBA-RS measurements were found significantly increased in midbrain, liver, and erythrocytes of GA-injected rats. The activity of GPx was significantly reduced in midbrain and markedly increased in liver. TAR measurement was significantly reduced in midbrain and liver. Furthermore, GSH levels were reduced in liver and heart. We also investigated the acute in vivo effect of GA administration on the same oxidative stress parameters in cerebral structures and erythrocytes from 22-day-old rats. We found that TBA-RS values were significantly increased in erythrocytes, TAR levels were markedly decreased in midbrain and cerebellum, and GPx activity mildly reduced in the midbrain.3. These data showing an imbalance between antioxidant defences and oxidative damage, particularly in midbrain, liver, and erythrocytes from GA-injected rats, indicate that oxidative stress might be involved in GA toxicity and that the midbrain, where the striatum is located, is the brain structure more susceptible to GA chronic and acute exposition.
authors.affiliation: Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Rua Ramiro Barcelos, 2600 Anexo, Porto Alegre, RS, Brazil.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Latini
authors.forename: Gustavo C
authors.initials: GC
authors.lastname: Ferreira
authors.forename: Karina
authors.initials: K
authors.lastname: Scussiato
authors.forename: Patrícia F
authors.initials: PF
authors.lastname: Schuck
authors.forename: Alexandre F
authors.initials: AF
authors.lastname: Solano
authors.forename: Carlos S
authors.initials: CS
authors.lastname: Dutra-Filho
authors.forename: Carmen R
authors.initials: CR
authors.lastname: Vargas
authors.forename: Moacir
authors.initials: M
authors.lastname: Wajner
mesh_terms: D000279:Administration, Cutaneous; D000818:Animals; D000831:Animals, Newborn; D000975:Antioxidants / Q000032:analysis; D001921:Brain / Q000378:metabolism; D001923:Brain Chemistry / Q000187:drug effects; D002374:Catalase / Q000032:analysis / Q000097:blood; D004305:Dose-Response Relationship, Drug; D004912:Erythrocytes / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D005977:Glutarates / Q000008:administration & dosage / Q000633:toxicity*; D005978:Glutathione / Q000032:analysis / Q000097:blood; D005979:Glutathione Peroxidase / Q000378:metabolism; D008297:Male; D018482:Muscle, Skeletal / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects*; D051381:Rats; D017208:Rats, Wistar; D017392:Thiobarbituric Acid Reactive Substances / Q000032:analysis
chemical_list: D000975:Antioxidants; D005977:Glutarates; D017392:Thiobarbituric Acid Reactive Substances; D002374:Catalase; D005979:Glutathione Peroxidase; D005978:Glutathione; C035736:glutaric acid