title: Intravenous immunoglobulin (IVIG) protects the brain against experimental stroke by preventing complement-mediated neuronal cell death.
abstract: Stroke is among the three leading causes of death worldwide and the most frequent cause of permanent disability. Brain ischemia induces an inflammatory response involving activated complement fragments. Here we show that i.v. Ig (IVIG) treatment, which scavenges complement fragments, protects brain cells against the deleterious effects of experimental ischemia and reperfusion (I/R) and prevents I/R-induced mortality in mice. Animals administered IVIG either 30 min before ischemia or after 3 h of reperfusion exhibited a 50-60% reduction of brain infarct size and a 2- to 3-fold improvement of the functional outcome. Even a single low dose of IVIG given after stroke was effective. IVIG was protective in the nonreperfusion model of murine stroke as well and did not exert any peripheral effects. Human IgG as well as intrinsic murine C3 levels were significantly higher in the infarcted brain region compared with the noninjured side, and their physical association was demonstrated by immuno-coprecipitation. C5-deficient mice were significantly protected from I/R injury compared with their wild-type littermates. Exposure of cultured neurons to oxygen/glucose deprivation resulted in increased levels of C3 associated with activation of caspase 3, a marker of apoptosis; both signals were attenuated with IVIG treatment. Our data suggest a major role for complement-mediated cell death in ischemic brain injury and the prospect of using IVIG in relatively low doses as an interventional therapy for stroke.
authors: Laboratory of Neurosciences, National Institute on Aging Intramural Research Program, 5600 Nathan Shock Drive, Baltimore, MD 21224, USA.
authors: Thiruma V
authors: TV
authors: Arumugam
authors: Sung-Chun
authors: SC
authors: Tang
authors: Justin D
authors: JD
authors: Lathia
authors: Aiwu
authors: A
authors: Cheng
authors: Mohamed R
authors: MR
authors: Mughal
authors: Srinivasulu
authors: S
authors: Chigurupati
authors: Tim
authors: T
authors: Magnus
authors: Sic L
authors: SL
authors: Chan
authors: Dong-Gyu
authors: DG
authors: Jo
authors: Xin
authors: X
authors: Ouyang
authors: David P
authors: DP
authors: Fairlie
authors: Daniel N
authors: DN
authors: Granger
authors: Alexander
authors: A
authors: Vortmeyer
authors: Milan
authors: M
authors: Basta
authors: Mark P
authors: MP
authors: Mattson
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000276:immunology / Q000473:pathology; D016923:Cell Death / Q000187:drug effects*; D002540:Cerebral Cortex / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D002544:Cerebral Infarction / Q000276:immunology / Q000517:prevention & control*; D003182:Complement C5 / Q000172:deficiency; D004195:Disease Models, Animal; D004334:Drug Administration Schedule; D016756:Immunoglobulins, Intravenous / Q000627:therapeutic use*; D007155:Immunologic Factors / Q000627:therapeutic use; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000187:drug effects / Q000473:pathology*
chemical_list: D003182:Complement C5; D016756:Immunoglobulins, Intravenous; D007155:Immunologic Factors
references: Exp Neurol. 2000 Jan;161(1):373-82
references: 10683302
references: Nat Med. 2003 Apr;9(4):431-8
references: 12612546
references: Ann Neurol. 2005 May;57(5):758-61
references: 15852374
references: Eur J Pharmacol. 2001 Oct 5;428(2):193-201
references: 11675036
references: Stroke. 2001 Feb;32(2):553-60
references: 11157196
references: Thromb Haemost. 2006 Oct;96(4):529-34
references: 17003933
references: Curr Top Microbiol Immunol. 1990;153:181-208
references: 2404694
references: Saudi Med J. 2002 Jan;23(1):13-9
references: 11938357
references: J Am Coll Cardiol. 1987 Sep;10(3):627-32
references: 3114350
references: J Med Chem. 1999 Jun 3;42(11):1965-74
references: 10354404
references: Nature. 1989 May 25;339(6222):314-7
references: 2725646
references: J Hypertens Suppl. 2003 Jun;21(5):S3-7
references: 12953849
references: J Neurosci. 1992 Feb;12(2):376-89
references: 1346802
references: Clin Rev Allergy Immunol. 2005 Dec;29(3):173-84
references: 16391392
references: Immunopharmacology. 1992 Sep-Oct;24(2):135-48
references: 1473964
references: Brain Res. 1998 Aug 31;804(1):105-13
references: 9729310
references: Brain Res Bull. 1994;35(1):51-6
references: 7953757
references: Stroke. 1986 May-Jun;17(3):472-6
references: 3715945
references: JAMA. 1999 Dec 1;282(21):2019-26
references: 10591384
references: J Neurosci Methods. 1996 Dec 28;70(2):195-200
references: 9007759
references: Neurosci Lett. 2005 May 20-27;380(1-2):48-53
references: 15854749
references: Mol Med. 2001 Jun;7(6):367-82
references: 11474130
references: Mol Immunol. 2001 Aug;38(2-3):207-19
references: 11532282
references: Clin Exp Immunol. 1996 May;104 Suppl 1:21-5
references: 8625538
references: Inflammation. 1996 Feb;20(1):1-9
references: 8926043
references: J Neurochem. 2002 Nov;83(3):515-24
references: 12390513
references: J Cereb Blood Flow Metab. 2002 Apr;22(4):431-43
references: 11919514
references: Ann Neurol. 1996 Oct;40(4):587-96
references: 8871578