title: Polyinosinic-polycytidylic acid has therapeutic effects against cerebral ischemia/reperfusion injury through the downregulation of TLR4 signaling via TLR3.
abstract: Recent reports have shown that preconditioning with the TLR3 ligand polyinosinic-polycytidylic acid (poly(I:C)) protects against cerebral ischemia/reperfusion (I/R) injury. However, it is unclear whether poly(I:C) treatment after cerebral I/R injury is also effective. We used mouse/rat middle cerebral artery occlusion and cell oxygen-glucose deprivation models to evaluate the therapeutic effects and mechanisms of poly(I:C) treatment. Poly(I:C) was i.p. injected 3 h after ischemia (treatment group). Cerebral infarct volumes and brain edemas were significantly reduced, and neurologic scores were significantly increased. TNF-α and IL-1β levels were markedly decreased, whereas IFN-β levels were greatly increased, in the ischemic brain tissues, cerebral spinal fluid, and serum. Injuries to hippocampal neurons and mitochondria were greatly reduced. The numbers of TUNEL-positive and Fluoro-Jade B(+) cells also decreased significantly in the ischemic brain tissues. Poly(I:C) treatment increased the levels of Hsp27, Hsp70, and Bcl2 and decreased the level of Bax in the ischemic brain tissues. Moreover, poly(I:C) treatment attenuated the levels of TNF-α and IL-1β in serum and cerebral spinal fluid of mice stimulated by LPS. However, the protective effects of poly(I:C) against cerebral ischemia were abolished in TLR3(-/-) and TLR4(-/-)mice. Poly(I:C) downregulated TLR4 signaling via TLR3. Poly(I:C) treatment exhibited obvious protective effects 14 d after ischemia and was also effective in the rat permanent middle cerebral artery occlusion model. The results suggest that poly(I:C) exerts therapeutic effects against cerebral I/R injury through the downregulation of TLR4 signaling via TLR3. Poly(I:C) is a promising new drug candidate for the treatment of cerebral infarcts.
authors.affiliation: Department of Neurology, Xinqiao Hospital, Third Military Medical University, Chongqing 40037, China;
authors.forename: Peng-Fei
authors.initials: PF
authors.lastname: Wang
authors.forename: Huang
authors.initials: H
authors.lastname: Fang
authors.forename: Jing
authors.initials: J
authors.lastname: Chen
authors.forename: Sen
authors.initials: S
authors.lastname: Lin
authors.forename: Yong
authors.initials: Y
authors.lastname: Liu
authors.forename: Xiao-Yi
authors.initials: XY
authors.lastname: Xiong
authors.forename: Yan-Chun
authors.initials: YC
authors.lastname: Wang
authors.forename: Ren-Ping
authors.initials: RP
authors.lastname: Xiong
authors.forename: Feng-Lin
authors.initials: FL
authors.lastname: Lv
authors.forename: Jian
authors.initials: J
authors.lastname: Wang
authors.forename: Qing-Wu
authors.initials: QW
authors.lastname: Yang
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology*; D002545:Brain Ischemia / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology / Q000473:pathology; D015536:Down-Regulation / Q000187:drug effects* / Q000235:genetics / Q000276:immunology; D055551:HSP27 Heat-Shock Proteins / Q000235:genetics / Q000276:immunology; D018840:HSP70 Heat-Shock Proteins / Q000235:genetics / Q000276:immunology; D053583:Interleukin-1beta / Q000235:genetics / Q000276:immunology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D011070:Poly I-C / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D013997:Time Factors; D051196:Toll-Like Receptor 3 / Q000235:genetics / Q000276:immunology*; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000276:immunology
chemical_list: D000998:Antiviral Agents; D055551:HSP27 Heat-Shock Proteins; D018840:HSP70 Heat-Shock Proteins; C486114:Hspb1 protein, rat; C486699:Hspb2 protein, mouse; D053583:Interleukin-1beta; C519703:TLR3 protein, mouse; C530472:TLR3 protein, rat; C493487:Tlr4 protein, mouse; C495347:Tlr4 protein, rat; D051196:Toll-Like Receptor 3; D051197:Toll-Like Receptor 4; D014409:Tumor Necrosis Factor-alpha; D011070:Poly I-C
references.citation: Nat Med. 2012 Jun;18(6):911-7
references.pmid: 22610280
references.citation: Stroke. 2004 Sep;35(9):2189-94
references.pmid: 15256676
references.citation: Stroke. 2012 May;43(5):1383-9
references.pmid: 22403050
references.citation: BMC Neurosci. 2009 Sep 03;10:111
references.pmid: 19725984
references.citation: Front Immunol. 2012 May 31;3:132
references.pmid: 22833743
references.citation: Ann Neurol. 2011 Jan;69(1):119-29
references.pmid: 21280082
references.citation: J Neurosci. 2013 Jul 17;33(29):12041-51
references.pmid: 23864690
references.citation: Stroke. 1999 Dec;30(12):2752-8
references.pmid: 10583007
references.citation: Circulation. 2011 Feb 1;123(4):e18-e209
references.pmid: 21160056
references.citation: Biochem Biophys Res Commun. 2007 Feb 9;353(2):509-14
references.pmid: 17188246
references.citation: Anesthesiology. 2006 Nov;105(5):990-8
references.pmid: 17065894
references.citation: Braz J Med Biol Res. 2010 Nov;43(11):1027-33
references.pmid: 20945038
references.citation: Cell. 2010 Mar 19;140(6):805-20
references.pmid: 20303872
references.citation: Neuron. 2010 Jul 29;67(2):181-98
references.pmid: 20670828
references.citation: Nat Clin Pract Cardiovasc Med. 2009 Mar;6(3):164-5
references.pmid: 19153559
references.citation: J Neuroimmunol. 2007 Oct;190(1-2):28-33
references.pmid: 17854911
references.citation: Acta Pharmacol Sin. 2012 Oct;33(10):1246-53
references.pmid: 22983393
references.citation: Nat Med. 2011 Jul 07;17(7):796-808
references.pmid: 21738161
references.citation: J Immunol. 2009 Jul 15;183(2):1099-109
references.pmid: 19581626
references.citation: Neurobiol Dis. 2004 Dec;17(3):516-23
references.pmid: 15571987
references.citation: J Cereb Blood Flow Metab. 2005 Feb;25(2):217-25
references.pmid: 15678124
references.citation: Int Neurourol J. 2010 Dec;14(4):203-12
references.pmid: 21253330
references.citation: J Neuroimmunol. 2008 Aug 13;199(1-2):75-82
references.pmid: 18585792
references.citation: Stroke. 2009 May;40(5):e331-9
references.pmid: 19182083
references.citation: J Cereb Blood Flow Metab. 2011 Feb;31(2):593-605
references.pmid: 20700129
references.citation: Circulation. 2007 Mar 27;115(12):1599-608
references.pmid: 17372179
references.citation: J Neuroinflammation. 2011 Oct 14;8:140
references.pmid: 21999375
references.citation: Nat Rev Neurol. 2012 Jun 05;8(7):401-10
references.pmid: 22664787
references.citation: J Cereb Blood Flow Metab. 2012 Feb;32(2):242-7
references.pmid: 22086194
references.citation: Biochem Pharmacol. 2006 Oct 30;72(9):1102-13
references.pmid: 16930560
references.citation: Stroke. 1995 Jul;26(7):1252-7; discussion 1257-8
references.pmid: 7541573
references.citation: Eur J Heart Fail. 2008 Mar;10(3):233-43
references.pmid: 18321777
references.citation: Neuroscience. 2010 Nov 24;171(1):258-67
references.pmid: 20804821
references.citation: J Biol Chem. 2013 Jan 25;288(4):2756-66
references.pmid: 23212905
references.citation: J Cereb Blood Flow Metab. 2008 May;28(5):1040-7
references.pmid: 18183029
references.citation: Nat Immunol. 2008 Apr;9(4):369-77
references.pmid: 18345001
references.citation: N Engl J Med. 1995 Dec 14;333(24):1581-7
references.pmid: 7477192
references.citation: J Neuroimmunol. 2007 Oct;190(1-2):101-11
references.pmid: 17884182
references.citation: J Neurosci. 2008 Dec 3;28(49):13038-55
references.pmid: 19052195
references.citation: Proc Natl Acad Sci U S A. 2005 Nov 22;102(47):17077-82
references.pmid: 16287979
references.citation: Brain Res Mol Brain Res. 2002 Oct 15;106(1-2):101-16
references.pmid: 12393270
references.citation: Ann N Y Acad Sci. 2010 Oct;1207:32-40
references.pmid: 20955423
references.citation: Stroke. 2002 Mar;33(3):816-24
references.pmid: 11872909
references.citation: Ann Neurol. 2009 Sep;66(3):378-89
references.pmid: 19551849
references.citation: J Immunol. 2011 Aug 1;187(3):1458-66
references.pmid: 21709150
references.citation: Stroke. 1996 Sep;27(9):1616-22; discussion 1623
references.pmid: 8784138