Journal
ANNALS OF NEUROLOGY
Volume 61, Issue 4, Pages 352-362Publisher
WILEY
DOI: 10.1002/ana.21097
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Funding
- NINDS NIH HHS [1 R01 NS052791, 1 R01 NS39378] Funding Source: Medline
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Objective: 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. Methods: 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 gamma (PPAR gamma) in microglia/macrophages. Results: Our study demonstrated that the PPAR gamma 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 PPAR gamma activators. PPAR gamma activators significantly increased PPAR gamma-regulated gene (catalase and CD36) expression, whereas reducing proinflammatory gene (tumor necrosis factor-alpha, interleukin-1 beta, matrix metalloproteinase-9, and inducible nitric oxide synthase) expression, extracellular H2O2 level, and neuronal damage. Phagocytosis by microglia was significantly inhibited by PPAR gamma gene knockdown or neutralizing anti-CD36 antibody, whereas it was enhanced by exogenous catalase. Interpretation: PPAR gamma in macrophages acts as an important factor in promoting hematoma absorption and protecting other brain cells from ICH-induced damage.
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