title: Disruption of redox homeostasis and histopathological alterations caused by in vivo intrastriatal administration of D-2-hydroxyglutaric acid to young rats.
abstract: High accumulation of D-2-hydroxyglutaric acid (D-2-HG) is the biochemical hallmark of patients affected by the inherited neurometabolic disorder D-2-hydroxyglutaric aciduria (D-2-HGA). Clinically, patients present neurological symptoms and basal ganglia injury whose pathophysiology is poorly understood. We investigated the ex vivo effects of intrastriatal administration of D-2-HG on important parameters of redox status in the striatum of weaning rats. D-2-HG in vivo administration increased malondialdehyde (MDA) and carbonyl formation (lipid and protein oxidative damage, respectively), as well as the production of reactive nitrogen species (RNS). D-2-HG also compromised the antioxidant defenses by decreasing reduced glutathione (GSH) concentrations, as well as the activities of superoxide dismutase (SOD) and glutathione peroxidase (GPx). Increased amounts of oxidized glutathione (GSSG) with no significant alteration of total glutathione (tGS) were also found. Furthermore, D-2-HG-induced lipid oxidation and reduction of GSH concentrations and GPx activity were prevented by the N-methyl-d-aspartate (NMDA) receptor antagonist dizocilpine maleate (MK-801) and the nitric oxide synthase (NOS) inhibitor N(ω)-nitro-l-arginine methyl ester (l-NAME), suggesting the participation of NMDA receptors and nitric oxide derivatives in these effects. Creatine also impeded D-2-HG-elicited MDA increase, but did not change the D-2-HG-induced diminution of GSH and of the activities of SOD and GPx. We also found that DCFH oxidation and H2O2 production were not altered by D-2-HG, making unlikely an important role for reactive oxygen species (ROS) and reinforcing the participation of RNS in the oxidative damage and the reduction of antioxidant defenses provoked by this organic acid. Vacuolization, lymphocytic infiltrates and macrophages indicating brain damage were also observed in the striatum of rats injected with D-2-HG. The present data provide in vivo solid evidence that D-2-HG disrupts redox homeostasis and causes histological alterations in the rat striatum probably mediated by NMDA overstimulation and RNS production. It is therefore presumed that disturbance of redox status may contribute at least in part to the basal ganglia alterations characteristic of patients affected by D-2-HGA.
authors.affiliation: Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil.
authors.forename: M S
authors.initials: MS
authors.lastname: da Rosa
authors.affiliation: Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil.
authors.forename: B
authors.initials: B
authors.lastname: Seminotti
authors.affiliation: Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil.
authors.forename: A U
authors.initials: AU
authors.lastname: Amaral
authors.affiliation: Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil.
authors.forename: B
authors.initials: B
authors.lastname: Parmeggiani
authors.affiliation: Serviço de Patologia, Hospital de Clínicas de Porto Alegre, Porto Alegre, RS, Brazil.
authors.forename: F H
authors.initials: FH
authors.lastname: de Oliveira
authors.affiliation: Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil.
authors.forename: G
authors.initials: G
authors.lastname: Leipnitz
authors.affiliation: Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil; Serviço de Genética Médica, Hospital de Clínicas de Porto Alegre, Porto Alegre, RS, Brazil. Electronic address: mwajner@ufrgs.br.
authors.forename: M
authors.initials: M
authors.lastname: Wajner
mesh_terms: D000818:Animals; D003342:Corpus Striatum / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D003401:Creatine / Q000494:pharmacology; D016291:Dizocilpine Maleate / Q000494:pharmacology; D005977:Glutarates / Q000378:metabolism / Q000494:pharmacology / Q000633:toxicity*; D005978:Glutathione / Q000378:metabolism; D015227:Lipid Peroxidation / Q000187:drug effects / Q000502:physiology; D008315:Malondialdehyde / Q000378:metabolism; D016202:N-Methylaspartate / Q000378:metabolism; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D018696:Neuroprotective Agents / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D051381:Rats; D026361:Reactive Nitrogen Species / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D005977:Glutarates; D018696:Neuroprotective Agents; D026361:Reactive Nitrogen Species; D017382:Reactive Oxygen Species; C019417:alpha-hydroxyglutarate; D008315:Malondialdehyde; C022034:3-methylglutaconic acid; D016202:N-Methylaspartate; D016291:Dizocilpine Maleate; D005978:Glutathione; D003401:Creatine; D019331:NG-Nitroarginine Methyl Ester
keywords: D-2-hydroxyglutaric acid; D-2-hydroxyglutaric aciduria; brain damage; redox homeostasis; striatum