Background and Purpose— In humans, intracerebral hemorrhage (ICH) causes marked perihematomal edema formation and neurological deficits. A rat ICH model, involving infusion of autologous blood into the caudate, has been used extensively to study mechanisms of edema formation, but an examination of behavioral outcome would improve its preclinical utility and provide a more rigorous assessment of the pathological cascade of events over time. The purpose of this study was to use a battery of sensorimotor function tests to examine the neurological effects of ICH in the rat and to examine which components of the hematoma are involved in generating those effects. Methods— The behavioral tests used were forelimb placing, preference for forelimb use for weight shifts during vertical exploration of a cylindrical enclosure, and a corner turn test. Rats were tested from day 1 to day 28 after injection of autologous whole blood; injection of blood plus hirudin (thrombin inhibitor), packed red blood cells, thrombin, or saline; or needle placement only. Results— The battery of tests indicated that there were marked neurological deficits by day 1 after ICH, with progressive recovery of function over 4 weeks. The forelimb placing score paralleled changes in edema. Injection of thrombin caused and injection of hirudin reduced the ICH-induced neurological deficits. Injection of packed red blood cells, which causes delayed edema formation, induced delayed neurological deficits Conclusions— These tests allow continuous monitoring of neurological deficits after rat ICH and assessment of therapeutic interventions. The time course of the neurological deficit closely matched the time course of cerebral edema for both ICH and injection of blood components. There was marked recovery of function after ICH, which may be amenable to therapeutic manipulation.

This article reviews current knowledge of the mechanisms underlying the initial hemorrhage and secondary blood–brain barrier (BBB) dysfunction in primary spontaneous intracerebral hemorrhage (ICH) in adults. Multiple etiologies are associated with ICH, for example, hypertension, Alzheimer’s disease, vascular malformations and coagulopathies (genetic or drug-induced). After the initial bleed, there can be continued bleeding over the first 24 hours, so-called hematoma expansion, which is associated with adverse outcomes. A number of clinical trials are focused on trying to limit such expansion. Significant progress has been made on the causes of BBB dysfunction after ICH at the molecular and cell signaling level. Blood components (e.g. thrombin, hemoglobin, iron) and the inflammatory response to those components play a large role in ICH-induced BBB dysfunction. There are current clinical trials of minimally invasive hematoma removal and iron chelation which may limit such dysfunction. Understanding the mechanisms underlying the initial hemorrhage and secondary BBB dysfunction in ICH is vital for developing methods to prevent and treat this devastating form of stroke.

Background and Purpose—: Our previous studies found that erythrocyte CD47 has a role in regulating hematoma resolution following experimental intracerebral hemorrhage (ICH). The current study examined whether or not a CD47 blocking antibody enhances hematoma clearance in a mouse ICH. Methods—: ICH was induced by intracaudate injection of autologous blood in adult C57BL/6 mice. Mice had an ICH or ICH with CD47 blocking antibody or IgG coinjection. In subgroups of CD47 blocking antibody-treated mice, clodronate (to deplete microglia/macrophages) or control liposomes were coinjected. The effects of CD47 blocking antibody on ICH-induced brain injury were also tested in both males and females. Mice had magnetic resonance imaging to examine clot volume, iron deposition, brain swelling, and brain tissue loss. Behavioral tests were performed in all mice, and brains were harvested for brain immunohistochemistry. Results—: In male mice, CD47 blocking antibody speeded up hematoma/iron clearance by macrophages/microglia and reduced ICH-induced brain swelling, neuronal loss, and neurological deficits. In contrast, clodronate liposome-induced microglia/macrophage depletion caused more severe brain swelling, neuronal loss, and functional deficits. In addition, similar injury severity in males and females was found in IgG control group and CD47 blocking antibody was also effective in females. Conclusions—: Blocking CD47 in the hematoma speeded hematoma clearance and reduced brain injury after ICH suggesting it could be a treatment for ICH patients with surgical clot removal.

Background and Purpose—: Enhancing hematoma clearance through phagocytosis may reduce brain injury after intracerebral hemorrhage. In the current study, we investigated the role of cluster of differentiation 47 (CD47) in regulating erythrophagocytosis and brain injury after intracerebral hemorrhage in nude mice. Methods—: This study was in 2 parts. First, male adult nude mice had an intracaudate injection of 30 μL saline, blood from male adult wild-type (WT) mice, or blood from CD47 knockout mice. Second, mice had an intracaudate injection of 30 μL CD47 knockout blood with clodronate or control liposomes. Clodronate liposomes were also tested in saline-injected mice. All mice then had magnetic resonance imaging to measure hematoma size and brain swelling. Brains were used for immunohistochemistry and Western blot. Results—: Erythrophagocytosis occurred in and around the hematoma. Injection of CD47 knockout blood resulted in quicker clot resolution, less brain swelling, and less neurological deficits compared with wild-type blood. Higher brain heme oxygenase-1 levels and more microglial activation (mostly M2 polarized microglia) at day 3 were found after CD47 knockout blood injection. Co-injection of clodronate liposomes, to deplete phagocytes, caused more severe brain swelling and less clot resolution. Conclusions—: These results indicated that CD47 has a key role in hematoma clearance after intracerebral hemorrhage.