title: Glutathione peroxidase contributes with heme oxygenase-1 to redox balance in mouse brain during the course of cerebral malaria.
abstract: Oxidative stress has been attributed both a key pathogenic and rescuing role in cerebral malaria (CM). In a Plasmodium berghei ANKA murine model of CM, host redox signaling and functioning were examined during the course of neurological damage. Host antioxidant defenses were early altered at the transcriptional level indicated by the gradually diminished expression of superoxide dismutase-1 (sod-1), sod-2, sod-3 and catalase genes. During severe disease, this led to the dysfunctional activity of superoxide dismutase and catalase enzymes in damaged brain regions. Vitagene associated markers (heat shock protein 70 and thioredoxin-1) also showed a decaying expression pattern that paralleled reduced expression of the transcription factors Parkinson disease 7, Forkhead box O 3 and X-box binding protein 1 with a role in preserving brain redox status. However, the oxidative stress markers reactive oxygen/nitrogen species were not accumulated in the brains of CM mice and redox proteomics and immunohistochemistry failed to detect quantitative or qualitative differences in protein carbonylation. Thus, the loss of antioxidant capacity was compensated for in all cerebral regions by progressive upregulation of heme oxygenase-1, and in specific regions by early glutathione peroxidase-1 induction. This study shows for the first time a scenario of cooperative glutathione peroxidase and heme oxygenase-1 upregulation to suppress superoxide dismutase, catalase, heat shock protein-70 and thioredoxin-1 downregulation effects in experimental CM, counteracting oxidative damage and maintaining redox equilibrium. Our findings reconcile the apparent inconsistency between the lack of oxidative metabolite build up and reported protective effect of antioxidant therapy against CM.
authors.affiliation: Departamento de Bioquímica y Biología Molecular IV and Instituto de Investigación Hospital 12 de Octubre, Universidad Complutense de Madrid, Ciudad Universitaria, 28040 Madrid, Spain.
authors.forename: María
authors.initials: M
authors.lastname: Linares
authors.forename: Patricia
authors.initials: P
authors.lastname: Marín-García
authors.forename: Gabriela
authors.initials: G
authors.lastname: Martínez-Chacón
authors.forename: Susana
authors.initials: S
authors.lastname: Pérez-Benavente
authors.forename: Antonio
authors.initials: A
authors.lastname: Puyet
authors.forename: Amalia
authors.initials: A
authors.lastname: Diez
authors.forename: José M
authors.initials: JM
authors.lastname: Bautista
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D015153:Blotting, Western; D001921:Brain / Q000378:metabolism / Q000473:pathology*; D002374:Catalase / Q000378:metabolism; D004195:Disease Models, Animal; D005978:Glutathione / Q000378:metabolism; D005979:Glutathione Peroxidase / Q000378:metabolism*; D051547:Heme Oxygenase-1 / Q000378:metabolism*; D016779:Malaria, Cerebral / Q000378:metabolism / Q000473:pathology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D050050:Protein Carbonylation; D026361:Reactive Nitrogen Species / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D013482:Superoxide Dismutase / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D000975:Antioxidants; D026361:Reactive Nitrogen Species; D017382:Reactive Oxygen Species; D014157:Transcription Factors; D002374:Catalase; D005979:Glutathione Peroxidase; D051547:Heme Oxygenase-1; D013482:Superoxide Dismutase; D005978:Glutathione
keywords: Experimental cerebral malaria; Oxidative stress; Redox balance; Redox proteomics