Intravenous immunoglobulin (IVIG) protects the brain against experimental stroke by preventing complement-mediated neuronal cell death.
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.
Arumugam
Thiruma V
TV
Laboratory of Neurosciences, National Institute on Aging Intramural Research Program, 5600 Nathan Shock Drive, Baltimore, MD 21224, USA.
Tang
Sung-Chun
SC
Lathia
Justin D
JD
Cheng
Aiwu
A
Mughal
Mohamed R
MR
Chigurupati
Srinivasulu
S
Magnus
Tim
T
Chan
Sic L
SL
Jo
Dong-Gyu
DG
Ouyang
Xin
X
Fairlie
David P
DP
Granger
Daniel N
DN
Vortmeyer
Alexander
A
Basta
Milan
M
Mattson
Mark P
MP
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*
D003182:Complement C5; D016756:Immunoglobulins, Intravenous; D007155:Immunologic Factors
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