Intravenous immunoglobulin (IVIG) protects the brain against experimental stroke by preventing complement-mediated neuronal cell death

Thiruma V. Arumugam, Sung Chun Tang, Justin D. Lathia, Aiwu Cheng, Mohamed R. Mughal, Srinivasulu Chigurupati, Tim Magnus, Sic L. Chan, Dong Gyu Jo, Xin Ouyang, David P. Fairlie, Daniel N. Granger, Alexander Vortmeyer, Milan Basta, Mark P. Mattson

Research output: Contribution to journalArticle

145 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)14104-14109
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume104
Issue number35
DOIs
StatePublished - Aug 28 2007

Keywords

  • C5a
  • Cerebral cortex apoptosis
  • Ischemic stroke
  • Lymphocyte
  • Microglia

ASJC Scopus subject areas

  • General

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    Arumugam, T. V., Tang, S. C., Lathia, J. D., Cheng, A., Mughal, M. R., Chigurupati, S., Magnus, T., Chan, S. L., Jo, D. G., Ouyang, X., Fairlie, D. P., Granger, D. N., Vortmeyer, A., Basta, M., & Mattson, M. P. (2007). Intravenous immunoglobulin (IVIG) protects the brain against experimental stroke by preventing complement-mediated neuronal cell death. Proceedings of the National Academy of Sciences of the United States of America, 104(35), 14104-14109. https://doi.org/10.1073/pnas.0700506104