title: In vivo experimental evidence that the major metabolites accumulating in 3-hydroxy-3-methylglutaryl-CoA lyase deficiency induce oxidative stress in striatum of developing rats: a potential pathophysiological mechanism of striatal damage in this disorder.
abstract: 3-Hydroxy-3-methylglutaryl-CoA lyase (HL) deficiency is a genetic disorder biochemically characterized by predominant accumulation of 3-hydroxy-3-methylglutaric (HMG) and 3-methylglutaric (MGA) acids in tissues and biological fluids of affected individuals. Clinically, the patients present neurological symptoms and basal ganglia injury, whose pathomechanisms are partially understood. In the present study, we investigated the ex vivo effects of intrastriatal administration of HMG and MGA on important parameters of oxidative stress in striatum of developing rats. Our results demonstrate that HMG and MGA induce lipid and protein oxidative damage. HMG and MGA also increased 2',7'-dichlorofluorescein oxidation, whereas only HMG elicited nitric oxide production, indicating a role for reactive oxygen (HMG and MGA) and nitrogen (HMG) species in these effects. Regarding the enzymatic antioxidant defenses, both organic acids decreased reduced glutathione concentrations and the activities of superoxide dismutase and glutathione reductase and increased glutathione peroxidase activity. HMG also provoked an increase of catalase activity and a diminution of glucose-6-phosphate dehydrogenase activity. We finally observed that antioxidants fully prevented or attenuated HMG-induced alterations of the oxidative stress parameters, further indicating the participation of reactive species in these effects. We also observed that MK-801, a non-competitive antagonist of the N-methyl-D-aspartate (NMDA) receptor, prevented some of these effects, indicating the involvement of the NMDA receptor in HMG effects. The present data provide solid evidence that oxidative stress is induced in vivo by HMG and MGA in rat striatum and it is presumed that this pathomechanism may explain, at least in part, the cerebral alterations observed in HL deficiency.
authors.affiliation: Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil.
authors.forename: Carolina Gonçalves
authors.initials: CG
authors.lastname: Fernandes
authors.forename: Mateus Struecker
authors.initials: MS
authors.lastname: da Rosa
authors.forename: Bianca
authors.initials: B
authors.lastname: Seminotti
authors.forename: Paula
authors.initials: P
authors.lastname: Pierozan
authors.forename: Rafael Wolter
authors.initials: RW
authors.lastname: Martell
authors.forename: Valeska Lizzi
authors.initials: VL
authors.lastname: Lagranha
authors.forename: Estela Natacha Brandt
authors.initials: EN
authors.lastname: Busanello
authors.forename: Guilhian
authors.initials: G
authors.lastname: Leipnitz
authors.forename: Moacir
authors.initials: M
authors.lastname: Wajner
mesh_terms: D000101:Acetyl-CoA C-Acetyltransferase / Q000172:deficiency* / Q000378:metabolism; D000592:Amino Acid Metabolism, Inborn Errors / Q000378:metabolism*; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D001479:Basal Ganglia / Q000254:growth & development / Q000378:metabolism* / Q000473:pathology; D002374:Catalase / Q000378:metabolism; D016291:Dizocilpine Maleate / Q000494:pharmacology; D005978:Glutathione / Q000378:metabolism; D005979:Glutathione Peroxidase / Q000378:metabolism; D008297:Male; D008315:Malondialdehyde / Q000378:metabolism; D015093:Meglutol / Q000031:analogs & derivatives* / Q000378:metabolism*; D018384:Oxidative Stress; D050050:Protein Carbonylation; D051381:Rats; D017208:Rats, Wistar; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors; D013482:Superoxide Dismutase / Q000378:metabolism; D014810:Vitamin E / Q000494:pharmacology
chemical_list: D000975:Antioxidants; D016194:Receptors, N-Methyl-D-Aspartate; D014810:Vitamin E; C033686:3-methylglutaric acid; D008315:Malondialdehyde; D016291:Dizocilpine Maleate; D015093:Meglutol; D002374:Catalase; D005979:Glutathione Peroxidase; D013482:Superoxide Dismutase; D000101:Acetyl-CoA C-Acetyltransferase; D005978:Glutathione