Hematoma Resolution as a Therapeutic Target
The Role of Microglia/Macrophages
Xiurong Zhao, MD; James Grotta, MD; Nicole Gonzales, MD; Jaroslaw Aronowski, PhD
Abstract—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. (Stroke. 2009;40[suppl 1]:S92-S94.)
Key Words: catalase ? CD36 ? intracerebral hemorrhage ? phagocytosis ? PPAR?
50% to 60%.1,2There is currently no US Food and Drug
Administration-approved treatment for ICH.
Although the majority of damage may occur within the first
few hours after ICH due to the mass effect of the hematoma, a
secondary cause of injury is due to the presence of intraparen-
chymal blood. The nature of this secondary damage is com-
plex, but it is caused primarily by the cytotoxic effect of
extravasated blood and by cytotoxic substances released by
activated neuroglia and hematogenous cells that invade the
brain.3,4This cytotoxic insult has a strong oxidative compo-
nent and ultimately leads to neuronal loss, gray matter damage,
vascular injury, blood–brain barrier disruption, and deadly brain
edema.3–10Because the presence of intraparenchymal blood is
the source of cytotoxic insult and inflammation, we propose that
secondary damage to the brain after ICH could be reduced by
augmenting removal of the intraparenchymal blood and anti-
inflammatory or cytoprotective agents.
We propose that peroxisome proliferator–activated
receptor-gamma (PPAR?), a transcription factor and pleio-
tropic mediator for cellular defense (cytoprotection) and a
stimulator for the scavenging system (hematoma clearance),
ntracerebral hemorrhage (ICH) accounts for 10% to 15%
of all strokes and has a 1-year mortality rate greater than
may represent a novel target for ICH therapy.11Hence, the
central hypothesis is that PPAR?, through mechanisms which
include upregulation of CD36 (the phagocytosis-facilitating
gene), promotes hematoma clearance. Faster hematoma res-
olution prevents secondary damage caused by the toxicity of
the hematoma and hematoma-induced inflammation.
In addition, PPAR? acts as a key genomic homeostatic
regulator for intracellular stress by promoting the transcrip-
tion of gene products that have a key role in antioxidative
defense such as catalase12and superoxide dismutase,13which
help not only to improve neuronal resistance, but also protect
microglia from damage, thus preserving their phagocytotic
(hematoma clearance) functions.
Receptor-Gamma Upregulates CD36 and
Promotes Microglia-Mediated Phagocytosis
Phagocytosis mediated by microglia and macrophages at the
site of brain injury is coordinated by a highly complex set of
proteins that mediates anchoring, internalization, and pro-
cessing of the phagocytotic targets. One well-recognized
Received and accepted July 30, 2008.
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@uth.tmc.edu
© 2009 American Heart Association, Inc.
Stroke is available at http://stroke.ahajournals.orgDOI: 10.1161/STROKEAHA.108.533158
by guest on September 24, 2015http://stroke.ahajournals.org/Downloaded from