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Lipopolysaccharide-Elicited Systemic Inflammation Induces Selective Vulnerability of Cerebral Cortex and Striatum of Developing Glutaryl-CoA Dehydrogenase Deficient (Gcdh -/- ) Mice to Oxidative Stress.

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  • Additional Information
    • Source:
      Publisher: Springer Country of Publication: United States NLM ID: 100929017 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1476-3524 (Electronic) Linking ISSN: 10298428 NLM ISO Abbreviation: Neurotox Res Subsets: MEDLINE
    • Publication Information:
      Publication: <2009-> : New York : Springer
      Original Publication: [Amsterdam?] : Harwood Academic Publishers,
    • Subject Terms:
      Cerebral Cortex/*metabolism ; Corpus Striatum/*metabolism ; Glutaryl-CoA Dehydrogenase/*deficiency ; Inflammation Mediators/*metabolism ; Lipopolysaccharides/*toxicity ; Oxidative Stress/*physiology; Animals ; Cerebral Cortex/drug effects ; Corpus Striatum/drug effects ; Dose-Response Relationship, Drug ; Female ; Male ; Mice ; Mice, 129 Strain ; Mice, Knockout ; Oxidative Stress/drug effects
    • Abstract:
      We investigated redox homeostasis in cerebral and peripheral tissues of wild type (WT) and glutaryl-CoA dehydrogenase knockout mice (Gcdh -/- ) submitted to inflammation induced by lipopolysaccharide (LPS) since patients with glutaric aciduria type I (GA I) manifest acute encephalopathy during catabolic events triggered by inflammation. WT and Gcdh -/- mice fed a low (0.9%) or high (4.7%) Lys chow were euthanized 4 h after LPS intraperitoneal injection. Cerebral cortex of Lys-restricted Gcdh -/- animals presented no alterations of redox homeostasis, whereas those fed a high Lys chow showed increased malondialdehyde (MDA) levels and superoxide dismutase (SOD) activity, compared to WT mice. Furthermore, Gcdh -/- mice receiving low Lys and injected with LPS presented elevated MDA levels and decreased reduced glutathione (GSH) concentrations, glutathione peroxidase (GPx), and glutathione reductase (GR) activities in cerebral cortex. LPS administration also decreased GSH values, as well as GPx and GR activities in cerebral cortex of Gcdh -/- mice receiving Lys overload. Further experiments performed in WT and Gcdh -/- mice injected with LPS and receiving either a low or high Lys chow revealed increased MDA levels and decreased GSH concentrations in cerebral cortex and striatum, but not in hippocampus, liver and heart of Gcdh -/- mice, suggesting a selective vulnerability of these cerebral structures to oxidative stress during an inflammatory process. LPS administration also increased S100B and NF-κF protein levels in brain of Gcdh -/- mice receiving high Lys. These data support the hypothesis that low Lys diet is beneficial in GA I by preventing redox imbalance, whereas a high Lys diet or systemic inflammation per se or combined induce oxidative stress in striatum and cerebral cortex that are mainly damaged in this disorder.
    • Grant Information:
      425914/2016-0 Conselho Nacional de Desenvolvimento Científico e Tecnológico; 2266-2551/14-2 Fundação de Amparo à Pesquisa do Estado do Rio Grande do Sul; 120420 Hospital de Clínicas de Porto Alegre; 01.06.0842-00 Financiadora de Estudos e Projetos; 573677/2008-5 Instituto Nacional de Ciência e Tecnologia para Excitotoxicidade e Neuroproteção
    • Contributed Indexing:
      Keywords: Cerebral cortex; Glutaric acidemia type I; Lipopolysaccharide; Oxidative stress; Striatum; Systemic inflammation
    • Accession Number:
      0 (Inflammation Mediators)
      0 (Lipopolysaccharides)
      EC 1.3.8.6 (Glutaryl-CoA Dehydrogenase)
    • Publication Date:
      Date Created: 20201001 Date Completed: 20210820 Latest Revision: 20210820
    • Publication Date:
      20250114
    • Accession Number:
      10.1007/s12640-020-00291-0
    • Accession Number:
      33001399