title: The regulatory role of NF-κB in autophagy-like cell death after focal cerebral ischemia in mice.
abstract: Autophagy may contribute to ischemia-induced cell death in the brain, but the regulation of autophagic cell death is largely unknown. Nuclear factor kappa B (NF-κB) is a regulator of apoptosis in cerebral ischemia. We examined the hypothesis that autophagy-like cell death could contribute to ischemia-induced brain damage and the process was regulated by NF-κB. In adult wild-type (WT) and NF-κB p50 knockout (p50(-/-)) mice, focal ischemia in the barrel cortex was induced by ligation of distal branches of the middle cerebral artery. Twelve to 24h later, autophagic activity increased as indicated by enhanced expression of Beclin-1 and LC3 in the ischemic core and/or penumbra regions. This increased autophagy contributed to cell injury, evidenced by terminal deoxynucleotidyltransferase (TdT)-mediated dUTP-biotin nick end labeling (TUNEL) co-staining and a protective effect achieved by the autophagy inhibitor 3-methyladenine. The number of Beclin-1/TUNEL-positive cells was significantly more in p50(-/-) mice than in WT mice. Neuronal and vascular cell death, as determined by TUNEL-positive cells co-staining with NeuN or Collagen IV, was more abundant in p50(-/-) mice. Immunostaining of the endothelial cell tight junction marker occludin revealed more damage to the blood-brain barrier in p50(-/-) mice. Western blotting of the peri-infarct tissue showed a reduction of Akt-the mammalian target of rapamycin (mTOR) signaling in p50(-/-) mice after ischemia. These findings provide the first evidence that cerebral ischemia induced autophagy-like injury is regulated by the NF-κB pathway, which may suggest potential treatments for ischemic stroke.
authors.affiliation: Department of Anesthesiology, Emory University School of Medicine, Atlanta, GA 30322, USA.
authors.forename: W-L
authors.initials: WL
authors.lastname: Li
authors.forename: S P
authors.initials: SP
authors.lastname: Yu
authors.forename: D
authors.initials: D
authors.lastname: Chen
authors.forename: S S
authors.initials: SS
authors.lastname: Yu
authors.forename: Y-J
authors.initials: YJ
authors.lastname: Jiang
authors.forename: T
authors.initials: T
authors.lastname: Genetta
authors.forename: L
authors.initials: L
authors.lastname: Wei
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D001343:Autophagy / Q000187:drug effects / Q000502:physiology*; D001812:Blood-Brain Barrier / Q000503:physiopathology; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D020244:Infarction, Middle Cerebral Artery / Q000378:metabolism / Q000503:physiopathology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000502:physiology*; D052002:NF-kappa B p50 Subunit / Q000235:genetics; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
chemical_list: D016328:NF-kappa B; D052002:NF-kappa B p50 Subunit; C025946:3-methyladenine; C546843:mTOR protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D000225:Adenine
references.citation: Brain Res. 2009 Jun 1;1273:129-37
references.pmid: 19362080
references.citation: Autophagy. 2008 May;4(4):524-6
references.pmid: 18367868
references.citation: Neurobiol Dis. 2008 Jan;29(1):132-41
references.pmid: 17936001
references.citation: Brain Res. 1996 Nov 11;739(1-2):343-9
references.pmid: 8955958
references.citation: Dev Cell. 2006 Dec;11(6):859-71
references.pmid: 17141160
references.citation: BMJ. 2005 Oct 15;331(7521):903
references.pmid: 16223828
references.citation: J Cereb Blood Flow Metab. 2000 Mar;20(3):592-603
references.pmid: 10724123
references.citation: Brain Res. 2004 Oct 1;1022(1-2):54-61
references.pmid: 15353213
references.citation: Autophagy. 2009 Feb;5(2):221-3
references.pmid: 19029804
references.citation: Front Biosci. 2008 Jan 01;13:718-36
references.pmid: 17981582
references.citation: Neuroscience. 2010 Mar 10;166(1):252-62
references.pmid: 19963043
references.citation: Oncogene. 2007 Jun 14;26(28):4071-83
references.pmid: 17213804
references.citation: Am J Physiol Cell Physiol. 2010 Apr;298(4):C776-85
references.pmid: 20089931
references.citation: J Neurosci. 2012 Jul 11;32(28):9588-600
references.pmid: 22787045
references.citation: Cytokine Growth Factor Rev. 2007 Jun-Aug;18(3-4):233-43
references.pmid: 17485237
references.citation: Am J Pathol. 2006 Aug;169(2):566-83
references.pmid: 16877357
references.citation: Autophagy. 2006 Jan-Mar;2(1):55-7
references.pmid: 16874065
references.citation: Autophagy. 2008 May;4(4):427-34
references.pmid: 18367871
references.citation: Neurosci Lett. 2010 Mar 8;471(3):152-6
references.pmid: 20100543
references.citation: Nat Rev Mol Cell Biol. 2005 Jun;6(6):439-48
references.pmid: 15928708
references.citation: Curr Opin Cell Biol. 2005 Dec;17(6):596-603
references.pmid: 16226444
references.citation: Stroke. 2008 Sep;39(9):2578-86
references.pmid: 18420947
references.citation: Cardiovasc Drugs Ther. 2006 Dec;20(6):445-62
references.pmid: 17149555
references.citation: FASEB J. 2012 Jul;26(7):2799-810
references.pmid: 22459147
references.citation: Stroke. 2004 Apr;35(4):987-91
references.pmid: 14988572
references.citation: Science. 2004 Nov 5;306(5698):990-5
references.pmid: 15528435
references.citation: Brain Res Bull. 2009 Aug 14;79(6):426-30
references.pmid: 19477244
references.citation: Dev Neurobiol. 2008 Nov;68(13):1474-86
references.pmid: 18777565
references.citation: Autophagy. 2007 Jul-Aug;3(4):390-2
references.pmid: 17471012
references.citation: Neuroscience. 2006;139(3):965-78
references.pmid: 16533569
references.citation: Curr Neurovasc Res. 2005 Dec;2(5):409-23
references.pmid: 16375722
references.citation: Autophagy. 2005 Apr;1(1):1-10
references.pmid: 16874026
references.citation: Brain Res. 2006 May 9;1088(1):167-75
references.pmid: 16630592
references.citation: Brain Res. 2008 Sep 16;1230:281-9
references.pmid: 18657523
references.citation: Am J Pathol. 2008 Feb;172(2):454-69
references.pmid: 18187572
references.citation: Cytokine Growth Factor Rev. 2006 Aug;17(4):281-93
references.pmid: 16793322
references.citation: Cell Signal. 2008 Apr;20(4):659-65
references.pmid: 18207367
references.citation: Exp Neurol. 2010 Jan;221(1):107-14
references.pmid: 19837065
references.citation: Acta Neurochir Suppl. 2008;105:105-12
references.pmid: 19066093
references.citation: Autophagy. 2010 Nov;6(8):1107-14
references.pmid: 20930570
references.citation: J Neuroimmune Pharmacol. 2006 Sep;1(3):223-36
references.pmid: 18040800
references.citation: Autophagy. 2007 Jan-Feb;3(1):42-4
references.pmid: 17035724
references.citation: FEBS J. 2009 Jan;276(1):36-45
references.pmid: 19087198
references.citation: J Pharmacol Exp Ther. 2006 Apr;317(1):109-16
references.pmid: 16357210
references.citation: J Cell Biol. 2008 Oct 6;183(1):101-16
references.pmid: 18838554
references.citation: Neurochem Res. 2007 Dec;32(12):2132-41
references.pmid: 17562165
references.citation: J Clin Invest. 2005 Oct;115(10):2679-88
references.pmid: 16200202
references.citation: Ann N Y Acad Sci. 2010 Oct;1207:32-40
references.pmid: 20955423
references.citation: Ann Neurol. 2009 Sep;66(3):378-89
references.pmid: 19551849
references.citation: Eur J Pharmacol. 2006 Sep 1;545(1):22-8
references.pmid: 16854410
references.citation: Autophagy. 2008 Aug;4(6):762-9
references.pmid: 18567942
references.citation: Mol Neurobiol. 2006 Dec;34(3):249-70
references.pmid: 17308356
references.citation: J Cereb Blood Flow Metab. 2010 Sep;30(9):1558-63
references.pmid: 20571520
references.citation: Cell. 2006 Feb 10;124(3):471-84
references.pmid: 16469695
references.citation: Cardiovasc Hematol Agents Med Chem. 2006 Oct;4(4):277-88
references.pmid: 17073605
references.citation: J Biol Chem. 2006 Oct 13;281(41):30373-82
references.pmid: 16857678