title: Time-dependent effects of systemic lipopolysaccharide injection on regulators of antioxidant defence Nrf2 and PGC-1α in the neonatal rat brain.
abstract: OBJECTIVE
  Both excitotoxicity and neuroinflammation are associated with oxidative stress. One transcription factor, nuclear factor E2-related factor 2 (Nrf2), and one transcription cofactor, peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α), increase the endogenous antioxidant defence and can thus modulate neuronal cell death. Here, we investigated the temporal effects (after 24 and 72 h) of systemic (i.p.) administration of lipopolysaccharide (LPS) on the cerebral Nrf2 and PGC-1α systems.
  
  
  RESULTS
  Seven-day-old rat pups were injected with LPS (0.3 mg/kg). After 24 h, the protein levels of γ-glutamylcysteine ligase modulatory subunit, γ-glutamylcysteine ligase catalytic subunit, Nrf2, PGC-1α and manganese superoxide dismutase (MnSOD) were increased in parallel with decreased levels of Keap1. These effects were correlated with an increased level of phosphorylated Akt and elevated acetylation of histone 4. In contrast, 72 h following LPS, a decrease in the components of the Nrf2 system in parallel with an increase in Keap1 was observed. The down-regulation after 72 h correlated with phosphorylation of p38 mitogen-activated protein kinase, while there were no changes in PGC-1α and MnSOD protein levels or the acetylation/methylation pattern of histones.
  
  
  CONCLUSIONS
  Systemic LPS in neonatal rats induced time-dependent changes in brain Nrf2 and PGC-1α that correlated well with the protective effect observed after 24 h (pre-conditioning) and the deleterious effects observed after 72 h (sensitizing) of systemic LPS reported earlier. Collectively, the results point towards Nrf2 and PGC-1α as a possible mechanism behind these effects.
authors: Department of Medical Biochemistry and Cell Biology, Institute of Biomedicine, University of Gothenburg, Sweden. Fernando.correa@medkem.gu.se
authors: Fernando
authors: F
authors: Correa
authors: Elin
authors: E
authors: Ljunggren
authors: Jaspal
authors: J
authors: Patil
authors: Xiaoyang
authors: X
authors: Wang
authors: Henrik
authors: H
authors: Hagberg
authors: Carina
authors: C
authors: Mallard
authors: Mats
authors: M
authors: Sandberg
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D000975:Antioxidants / Q000378:metabolism*; D001921:Brain / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D007249:Inflammation / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D007274:Injections, Intraperitoneal; D008070:Lipopolysaccharides / Q000008:administration & dosage / Q000633:toxicity*; D051267:NF-E2-Related Factor 2 / Q000096:biosynthesis*; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors; D014157:Transcription Factors / Q000096:biosynthesis*
chemical_list: D000975:Antioxidants; D008070:Lipopolysaccharides; D051267:NF-E2-Related Factor 2; C495637:Nfe2l2 protein, rat; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C501429:Ppargc1a protein, rat; D014157:Transcription Factors
references: J Biol Chem. 2000 Dec 22;275(51):39907-13
references: 10986282
references: PLoS One. 2011 Apr 29;6(4):e19456
references: 21559389
references: Chem Res Toxicol. 2005 Dec;18(12):1917-26
references: 16359182
references: Science. 1993 Oct 29;262(5134):689-95
references: 7901908
references: J Neurochem. 1996 May;66(5):2128-35
references: 8780045
references: Brain Res. 2011 Jan 25;1370:246-53
references: 21075092
references: Mol Neurodegener. 2009 Nov 16;4:47
references: 19917131
references: J Neurosci. 2005 Nov 2;25(44):10321-35
references: 16267240
references: J Neuropathol Exp Neurol. 2007 Jan;66(1):75-85
references: 17204939
references: Brain Res. 2009 Jul 28;1282:133-41
references: 19445907
references: Brain Res. 2010 Jul 9;1343:178-85
references: 20417626
references: Neurobiol Dis. 2011 Oct;44(1):142-51
references: 21757005
references: J Cereb Blood Flow Metab. 2010 Dec;30(12):1951-61
references: 20442725
references: J Biol Chem. 2008 Nov 21;283(47):32198-208
references: 18809684
references: Neurosci Lett. 2006 Jan 30;393(2-3):108-12
references: 16233958
references: Mol Cell. 2005 Aug 5;19(3):381-91
references: 16061184
references: Pediatr Res. 2005 Jul;58(1):112-6
references: 15879289
references: Mol Cell Biol. 2005 Aug;25(15):6592-602
references: 16024795
references: J Cereb Blood Flow Metab. 2000 Aug;20(8):1190-6
references: 10950379
references: Brain Res Dev Brain Res. 2000 Dec 29;125(1-2):51-60
references: 11154760
references: J Biol Chem. 2011 Mar 4;286(9):7629-40
references: 21196497
references: Pediatr Res. 2007 Apr;61(4):444-50
references: 17515869
references: Glia. 2011 May;59(5):785-99
references: 21351160
references: Antioxid Redox Signal. 2009 Mar;11(3):509-28
references: 18717631
references: Semin Fetal Neonatal Med. 2007 Aug;12(4):280-6
references: 17327146
references: Arch Pharm Res. 2011 Sep;34(9):1545-52
references: 21975817
references: Mol Cell Biochem. 2002 May-Jun;234-235(1-2):239-48
references: 12162440
references: Ann Neurol. 2007 Mar;61(3):263-71
references: 17253623
references: Am J Pathol. 2007 Jun;170(6):2068-76
references: 17525273
references: Proc Natl Acad Sci U S A. 2001 Apr 10;98(8):4611-6
references: 11287661
references: J Immunol. 2008 Jul 1;181(1):680-9
references: 18566435
references: J Immunol. 2009 Jun 1;182(11):7048-57
references: 19454702