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(Stroke. 2009;40:S92.)
© 2009 American Heart Association, Inc.

Brain Hemorrhage

Hematoma Resolution as a Therapeutic Target

The Role of Microglia/Macrophages

Xiurong Zhao, MD; James Grotta, MD; Nicole Gonzales, MD Jaroslaw Aronowski, PhD

From the Department of Neurology, University of Texas HSC-Houston, Stroke Program, Houston, Tex.

Correspondence to Jaroslaw Aronowski, PhD, Professor of Neurology, Director of Stroke Research, Department of Neurology, University of Texas-Houston Medical School, Houston, TX 77030. E-mail J.Aronowski{at}uth.tmc.edu

No effective therapy is available for treating intracerebral hemorrhage (ICH). One of several key components of brain damage after ICH is the neurotoxicity of blood products. Within hours to days after ICH, extravasated erythrocytes in the hematoma undergo lysis, releasing cytotoxic hemoglobin, heme, and iron, thereby initiating secondary processes, which negatively influence the viability of cells surrounding the hematoma. To offset this process, phagocytic cells, including the brain’s microglia and hematogenous macrophages, phagocytose and then process extravasated erythrocytes before lysis and subsequent toxicity occurs. Therefore, we hypothesize that a treatment that stimulates phagocytosis will lead to faster removal of blood from the ICH-affected brain, thus limiting/preventing hemolysis from occurring. CD36 is a well-recognized integral microglia/macrophage cell membrane protein known to mediate phagocytosis of damaged, apoptotic, or senescent cells, including erythrocytes. CD36 and catalase expression are regulated by peroxisome proliferator activated receptor-gamma agonists (eg, rosiglitazone). We demonstrate that peroxisome proliferator activated receptor-gamma agonist-induced upregulation of CD36 in macrophages enhances the ability of microglia to phagocytose red blood cells (in vitro assay), helps to improve hematoma resolution, and reduces ICH-induced deficit in a mouse model of ICH. The beneficial role of peroxisome proliferator activated receptor-gamma-induced catalase expression in the context of phagocytosis is also discussed. Proxisome proliferator activated receptor-gamma agonists could represent a potential treatment strategy for treatment of ICH.

Key Words: catalase • CD36 • intracerebral hemorrhage • phagocytosis • PPAR