Brain edema after experimental intracerebral hemorrhage: role of hemoglobin degradation products

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Object. The mechanisms involved in brain edema formation following intracerebral hemorrhage (ICH) have not been fully elucidated. The authors have found that red blood cell lysis plays an important role in edema development after ICH. In the present study, they sought to determine whether degradation products of hemoglobin cause brain edema.

Methods. Hemoglobin, hemin, bilirubin, or FeCl2 were infused with stereotactic guidance into the right basal ganglia of Sprague—Dawley rats. The animals were killed 24 hours later to determine brain water and ion contents. Western blot analysis and immunohistochemistry were applied for heme oxygenase-1 (HO-1) measurement. The effects of an HO inhibitor, tin-protoporphyrin (SnPP), and the iron chelator deferoxamine, on hemoglobin-induced brain edema were also examined.

Intracerebral infusion of hemoglobin, hemin, bilirubin, or FeCl2 caused an increase in brain water content at 24 hours. The HO-1 was upregulated after hemoglobin infusion and HO inhibition by SnPP-attenuated hemoglobin-induced edema. Brain edema induced by hemoglobin was also attenuated by the intraperitoneal injection of 500 mg/kg deferoxamine.

Conclusions. Hemoglobin causes brain edema, at least in part, through its degradation products. Limiting hemoglobin degradation coupled with the use of iron chelators may be a novel therapeutic approach to limit brain edema after ICH.

Article Information

Address reprint requests to: Guohua Xi, M.D., Room 5550 Kresge I, University of Michigan, Ann Arbor, Michigan 48109–0532. email: guohuaxi@umich.edu.

© AANS, except where prohibited by US copyright law.

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Figures

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    Photograph showing a coronal section of rat brain obtained 24 hours after a 30-µl hemoglobin infusion.

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    Bar graphs showing brain water (A) and sodium ion content (B) 24 hours after infusion of 30 µl of hemoglobin, hemin, bilirubin, or FeCl2. Values are expressed as the means ± SD. #p < 0.01 compared with the saline group.

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    Bar graph showing brain water contents in rats 24 hours after infusion of 30 µl of saline, vehicle, hemoglobin (Hb), or hemoglobin and SnPP. Values are expressed as the means ± SD. *p < 0.01 compared with saline or vehicle; **p < 0.05 compared with hemoglobin and SnPP; #p < 0.01 compared with the other groups.

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    Bar graph showing brain water content in rats 24 hours after infusion of 30 µl of hemoglobin (Hb). The animals received intraperitoneal injections of either 1 ml saline (control) or 50 mg/kg or 500 mg/kg deferoxamine ([DFX] in 1 ml saline) right after intracerebral infusion of hemoglobin. Values are expressed as the means ± SD. #p < 0.01 compared with the saline group.

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    Upper: The HO-1 levels were semiquantitated using Western blot analysis 24 hours after either saline control (lanes 1 to 3) or intracerebral infusion of hemoglobin (lanes 4 to 6). Lower: Bar graph depicting the results of Western blot analysis. Values are expressed as the means ± SD. #p < 0.01 compared with control.

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    Photomicrographs of rat brain sections showing HO-1 immunoactivities in the ipsilateral basal ganglia after sham operation (A) and hemoglobin infusion (B). Examples of HO-1 positive cells are indicated by arrows. Bar = 20 µm.

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