CD47 Blocking Antibody Accelerates Hematoma Clearance After Intracerebral Hemorrhage in Aged Rats
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ORIGINAL ARTICLE
CD47 Blocking Antibody Accelerates Hematoma Clearance After Intracerebral Hemorrhage in Aged Rats Chuanyuan Tao 1,2 & Richard F. Keep 1 & Guohua Xi 1 & Ya Hua 1 Received: 19 August 2019 / Revised: 25 September 2019 / Accepted: 26 September 2019 # Springer Science+Business Media, LLC, part of Springer Nature 2019
Abstract Both experimental studies and surgical clinical trials suggest that hematoma clearance is a therapeutic target in intracerebral hemorrhage (ICH). We have investigated effects of CD47, a “don’t eat me” signal expressed on erythrocytes, on hematoma resolution after ICH in young mice. This study expands those findings by examining the effects on a CD47 blocking antibody in aged rats. First, male Fischer 344 rats (18 months old) received an intracaudate injection of 50 μL autologous whole blood or saline. Hematoma features of magnetic resonance imaging (MRI) and neurological deficits were evaluated within 3 days. Second, rats had an intracaudate co-injection of 50 μL autologous blood with either CD47 blocking antibody or IgG. MRI was used to quantify hematoma/iron volume, hemolysis, brain swelling, and atrophy at different time points, behavioral tests to assess neurological deficits, and immunohistochemistry to assess brain injury and neuroinflammation. The CD47 blocking antibody significantly promoted hematoma clearance, attenuated brain swelling, hemolysis, and neuronal loss and increased the number of phagocytic macrophages in and around hematoma 3 days after ICH. Moreover, CD47 blockade reduced neuronal loss, brain atrophy, and neurobehavioral deficits at day 28. These results indicate that a CD47 blocking antibody can accelerate hematoma clearance and alleviate short- and long-term brain injury after ICH in aged rats and that it might be a therapeutic strategy for ICH. Keywords CD47 blocking antibody . Cerebral hemorrhage . Macrophage activation . Aged rats
Introduction Hematoma size is the strongest predictor of patient outc om e a f t e r in t r a ce r eb r al h e m o r r h ag e ( I C H ) [1] . Hematoma size will impact both the initial mass effect and the release of potentially neurotoxic factors from red blood cells (RBCs) [2]. Hence, hematoma reduction represents a key target in ICH treatment [3]. However, surgical hematoma evacuation failed to improve functional outcomes in ICH patients probably because of insufficient hematoma removal [4]. An alternative or complementary approach is to accelerate endogenous mechanisms involved in hematoma clearance [3]. Thus, stimulating phagocytosis via microglia/macrophage (M/MΦ) * Ya Hua [email protected] 1
Department of Neurosurgery, R5018 BSRB, University of Michigan, 109 Zina Pitcher Place, Ann Arbor, MI 48109-2200, USA
2
Department of Neurosurgery, West China Hospital, Sichuan University, Chengdu, China
activation with peroxisome proliferator-activated receptor-γ agonists accelerates hematoma clearance in murine ICH models [2, 5, 6]. CD47, a glycoprotein, is expressed on RBC membranes and acts as a “don’t eat me” signal. Low CD
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