Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
10832997 | Molecular Genetics and Metabolism | 2013 | 10 Pages |
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 2â²,7â²-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.
Keywords
GPXN-methyl-d-aspartateRNSDCFH-DADCFHSPSSGSSGMELMGAHmgHMGANACGSH3-methylglutaric acidNMDATBA-RS3-hydroxy-3-methylglutaric aciduriaDcfCATG6PDDNPHTCA2′,7′-dichlorofluorescein2′,7′-dichlorofluorescin diacetate2,4-dinitrophenylhydrazineGC/MSl-NAMENω-nitro-l-arginine methyl esterN-acetylcysteineROSStriatum3-hydroxy-3-methylglutaric acidtrichloroacetic acidStatistical Package for the Social SciencesOxidative stressSODSuperoxide dismutaseMelatoninCatalasereduced glutathionegas chromatography/mass spectrometryoxidized glutathioneglutathione reductaseglutathione peroxidaseglucose-6-phosphate dehydrogenasereactive nitrogen speciesReactive oxygen species
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Authors
Carolina Gonçalves Fernandes, Mateus Struecker da Rosa, Bianca Seminotti, Paula Pierozan, Rafael Wolter Martell, Valeska Lizzi Lagranha, Estela Natacha Brandt Busanello, Guilhian Leipnitz, Moacir Wajner,