Hematoma resolution as a target for intracerebral hemorrhage treatment: Role for peroxisome proliferator-activated receptor γ in microglia/macrophages
Article first published online: 24 APR 2007
Copyright © 2007 American Neurological Association
Annals of Neurology
Volume 61, Issue 4, pages 352–362, April 2007
How to Cite
Zhao, X., Sun, G., Zhang, J., Strong, R., Song, W., Gonzales, N., Grotta, J. C. and Aronowski, J. (2007), Hematoma resolution as a target for intracerebral hemorrhage treatment: Role for peroxisome proliferator-activated receptor γ in microglia/macrophages. Ann Neurol., 61: 352–362. doi: 10.1002/ana.21097
- Issue published online: 24 APR 2007
- Article first published online: 24 APR 2007
- Manuscript Accepted: 16 JAN 2007
- Manuscript Received: 1 SEP 2006
- National Institute of Neurological Disorders and Stroke. Grant Numbers: 1R01NS39378, 1R01NS052791
- American Heart Association. Grant Number: 0665200Y
Phagocytosis is necessary to eliminate the hematoma after intracerebral hemorrhage (ICH); however, release of proinflammatory mediators and free radicals during phagocyte activation is toxic to neighboring cells, leading to secondary brain injury. Promotion of phagocytosis in a timely and efficient manner may limit the toxic effects of persistent blood products on surrounding tissue and may be important for recovery after ICH.
Intrastriatal blood injection in rodents and primary microglia in culture exposed to red blood cells were used to model ICH and to study mechanisms of hematoma resolution and phagocytosis regulation by peroxisome proliferator-activated receptor γ (PPARγ) in microglia/macrophages.
Our study demonstrated that the PPARγ agonist, rosiglitazone, promoted hematoma resolution, decreased neuronal damage, and improved functional recovery in a mouse ICH model. Microglia isolated from murine brains showed more efficient phagocytosis in response to PPARγ activators. PPARγ activators significantly increased PPARγ-regulated gene (catalase and CD36) expression, whereas reducing proinflammatory gene (tumor necrosis factor-α, interleukin-1β, matrix metalloproteinase-9, and inducible nitric oxide synthase) expression, extracellular H2O2 level, and neuronal damage. Phagocytosis by microglia was significantly inhibited by PPARγ gene knockdown or neutralizing anti-CD36 antibody, whereas it was enhanced by exogenous catalase.
PPARγ in macrophages acts as an important factor in promoting hematoma absorption and protecting other brain cells from ICH-induced damage. Ann Neurol 2007;61:352–362