title: Ornithine In Vivo Administration Disrupts Redox Homeostasis and Decreases Synaptic Na(+), K (+)-ATPase Activity in Cerebellum of Adolescent Rats: Implications for the Pathogenesis of Hyperornithinemia-Hyperammonemia-Homocitrullinuria (HHH) Syndrome.
abstract: Hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome is an inborn error of metabolism caused by a defect in the transport of ornithine (Orn) into mitochondrial matrix leading to accumulation of Orn, homocitrulline (Hcit), and ammonia. Affected patients present a variable clinical symptomatology, frequently associated with cerebellar symptoms whose pathogenesis is poorly known. Although in vitro studies reported induction of oxidative stress by the metabolites accumulating in HHH syndrome, so far no report evaluated the in vivo effects of these compounds on redox homeostasis in cerebellum. Therefore, the present work was carried out to investigate the in vivo effects of intracerebellar administration of Orn and Hcit on antioxidant defenses (reduced glutathione concentrations and the activities of superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase, and glucose-6-phosphate dehydrogenase), lipid oxidation (malondialdehyde concentrations), as well as on the activity of synaptic Na(+), K(+)-ATPase, an enzyme highly vulnerable to free radical attack, in the cerebellum of adolescent rats. Orn significantly increased malondialdehyde levels and the activities of all antioxidant enzymes, and reduced Na(+), K(+)-ATPase activity. In contrast, glutathione concentrations were not changed by Orn treatment. Furthermore, intracerebellar administration of Hcit was not able to alter any of these parameters. The present data show for the first time that Orn provokes in vivo lipid oxidative damage, activation of the enzymatic antioxidant defense system, and reduction of the activity of a crucial enzyme involved in neurotransmission. It is presumed that these pathomechanisms may contribute at least partly to explain the neuropathology of cerebellum abnormalities and the ataxia observed in patients with HHH syndrome.
authors.affiliation: Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Rua Ramiro Barcelos No 2600 - Anexo, Porto Alegre, RS, CEP 90035-003, Brazil.
authors.forename: Ângela
authors.initials: Â
authors.lastname: Zanatta
authors.forename: Carolina Maso
authors.initials: CM
authors.lastname: Viegas
authors.forename: Fernanda Hermes
authors.initials: FH
authors.lastname: Hickmann
authors.forename: Wagner
authors.initials: W
authors.lastname: de Oliveira Monteiro
authors.forename: Angela
authors.initials: A
authors.lastname: Sitta
authors.forename: Daniela
authors.initials: D
authors.lastname: de Moura Coelho
authors.forename: Carmen Regla
authors.initials: CR
authors.lastname: Vargas
authors.forename: Guilhian
authors.initials: G
authors.lastname: Leipnitz
authors.forename: Moacir
authors.initials: M
authors.lastname: Wajner
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D002531:Cerebellum / Q000187:drug effects* / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D006706:Homeostasis / Q000187:drug effects; D022124:Hyperammonemia / Q000209:etiology* / Q000378:metabolism; D015227:Lipid Peroxidation / Q000187:drug effects; D008297:Male; D008315:Malondialdehyde / Q000378:metabolism; D009952:Ornithine / Q000008:administration & dosage / Q000172:deficiency* / Q000378:metabolism / Q000494:pharmacology*; D010084:Oxidation-Reduction / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D012741:Sexual Maturation / Q000502:physiology; D000254:Sodium-Potassium-Exchanging ATPase / Q000378:metabolism*; D013569:Synapses / Q000187:drug effects* / Q000378:metabolism; D056806:Urea Cycle Disorders, Inborn / Q000209:etiology* / Q000378:metabolism
chemical_list: D000975:Antioxidants; D008315:Malondialdehyde; D009952:Ornithine; D000254:Sodium-Potassium-Exchanging ATPase; D005978:Glutathione