Intracerebral hemorrhage (ICH) is a type of stroke caused by bleeding into the brain, which leads to significant death and disability. Secondary and delayed pathophysiologic events can contribute to the death and disability of the ICH patient. These events are characterized by a breakdown of the blood brain barrier, edema development and cell death in white and gray matter. We have recently discovered that following hemorrhage in the brain, a new molecular species, bilirubin oxidation species (BOXes), are produced within the hematoma during the first 24 hours following ICH. Importantly, the concentration of BOXes in the hematoma is the highest (approximately 20 iM) that we have observed in any of our experimental and clinical evaluations thus far. This finding is especially significant since we have previously demonstrated that BOXes are cytotoxic and our preliminary data indicates that they can contribute to the pathophysiological events leading to brain injury following ICH. Our overall goal in this research project is to test the Hypothesis that BOXes are acutely generated within the hematoma and contribute to edema formation and perihematomal brain injury following ICH. To address this hypothesis we will use our porcine ICH model.
In Aim #1 we will measure the concentration of BOXes in the hematoma and perihematomal brain tissue to define the time course of production.
In Aim #2 we will add BOXes to the infused blood to produce the hematoma and assess the damage and examine the underlying pathogenesis observed following experimental ICH.
In Aim #3 we will investigate the mechanism(s) for BOXes production by examining 2 biochemical pathways required to generate BOXes: bilirubin generation and oxidative stress. It is anticipated the inhibition of bilirubin production and/or antioxidants will decrease BOXes production in the hematoma. These studies are important because we believe that strategies designed to prevent BOXes production in the hematoma should provide a novel and beneficial therapeutic option for patients who have suffered an ICH.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS050569-04
Application #
7432522
Study Section
Special Emphasis Panel (ZRG1-BDCN-L (90))
Program Officer
Golanov, Eugene V
Project Start
2005-07-15
Project End
2010-05-31
Budget Start
2008-06-01
Budget End
2009-05-31
Support Year
4
Fiscal Year
2008
Total Cost
$336,575
Indirect Cost
Name
University of Cincinnati
Department
Neurology
Type
Schools of Medicine
DUNS #
041064767
City
Cincinnati
State
OH
Country
United States
Zip Code
45221
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Lu, A; Suofu, Y; Guan, F et al. (2013) Matrix metalloproteinase-2 deletions protect against hemorrhagic transformation after 1 h of cerebral ischemia and 23 h of reperfusion. Neuroscience 253:361-7
Suofu, Y; Clark, J F; Broderick, J P et al. (2012) Matrix metalloproteinase-2 or -9 deletions protect against hemorrhagic transformation during early stage of cerebral ischemia and reperfusion. Neuroscience 212:180-9
Loftspring, Matthew C; Johnson, Holly L; Feng, Rui et al. (2011) Unconjugated bilirubin contributes to early inflammation and edema after intracerebral hemorrhage. J Cereb Blood Flow Metab 31:1133-42
Hou, Shangwei; Xu, Rong; Clark, Joseph F et al. (2011) Bilirubin oxidation end products directly alter K+ channels important in the regulation of vascular tone. J Cereb Blood Flow Metab 31:102-12
Clark, Joseph F; Harm, Amanda; Saffire, Ashlie et al. (2011) Bilirubin oxidation products seen post subarachnoid hemorrhage have greater effects on aged rat brain compared to young. Acta Neurochir Suppl 110:157-62
Sa, Yalian; Hao, Jinsong; Samineni, Divya et al. (2011) Brain distribution and elimination of recombinant human TIMP-1 after cerebral ischemia and reperfusion in rats. Neurol Res 33:433-8
Loftspring, Matthew C; Hansen, Craig; Clark, Joseph F (2010) A novel brain injury mechanism after intracerebral hemorrhage: the interaction between heme products and the immune system. Med Hypotheses 74:63-6
Kurosawa, Yuko; Lu, Aigang; Khatri, Pooja et al. (2010) Intra-arterial iodinated radiographic contrast material injection administration in a rat middle cerebral artery occlusion and reperfusion model: possible effects on intracerebral hemorrhage. Stroke 41:1013-7
Suofu, Yalikun; Clark, Joseph; Broderick, Joseph et al. (2010) Peroxynitrite decomposition catalyst prevents matrix metalloproteinase activation and neurovascular injury after prolonged cerebral ischemia in rats. J Neurochem 115:1266-76

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