Subarachnoid hemorrhage (SAH) is a common subtype of stroke and the mortality rate is high (~35%) in the first several days. The causes of early brain injury following SAH are complicated including brain edema formation, blood-brain barrier disruption, increased intracranial pressure/brief global cerebral ischemia, and neurotoxicity caused by blood components. Research suggests that early brain injury following SAH is a primary therapeutic target. It is well known that the amount of blood released during SAH correlates with neurological deficits and poor clinical outcome. Although hemoglobin has been intensively studied as a potent factor for delayed vasospasm in SAH, the role of hemoglobin and its degradation products (especially iron) in SAH-induced early brain injury is not well studied. Our recent studies have demonstrated: 1) Brain iron overload occurs in a rat model of SAH;2) Deferoxamine, an iron chelator, reduces SAH-induced iron overload, oxidative stress and mortality;3) The complement cascade is activated and membrane attack complex levels are increased in the brain after experimental SAH which may play a role in erythrocyte lysis, iron overload and brain injury. However, major gaps in our knowledge regarding complement activation, erythrocyte lysis, brain iron overload and early brain injury after SAH need to be filled. In this application, therefore, we propose to examine the following Specific Aims: 1) To determine whether deferoxamine attenuates SAH-induced brain edema, blood-brain barrier disruption, hydrocephalus and vasospasm, major factors in SAH outcome;2) To determine whether blocking complement activation reduces erythrocyte lysis, brain iron accumulation and brain injury after SAH. The purpose of our project is to examine mechanisms of early brain injury after SAH. Data from the proposed studies may lead to new therapies for SAH. The long-term goal of our studies is to limit brain damage in SAH patients.

Public Health Relevance

After a brain hemorrhage, lysis of red blood cells causes a build up of iron in the brain. Brain iron accumulation can cause brain cell death and neurological deficits. Our recent studies found that iron chelation reduces brain iron levels and brain cell death in a rat model of subarachnoid hemorrhage. The purpose of this project is to investigate the mechanisms of early brain injury after subarachnoid hemorrhage. The long-term goal of our studies is to limit brain injury after hemorrhagic stroke.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS079157-03
Application #
8703823
Study Section
Brain Injury and Neurovascular Pathologies Study Section (BINP)
Program Officer
Koenig, James I
Project Start
2012-09-01
Project End
2017-07-31
Budget Start
2014-08-01
Budget End
2015-07-31
Support Year
3
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Neurosurgery
Type
Schools of Medicine
DUNS #
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
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Sun, Na; Keep, Richard F; Hua, Ya et al. (2016) Critical Role of the Sphingolipid Pathway in Stroke: a Review of Current Utility and Potential Therapeutic Targets. Transl Stroke Res 7:420-38
Dang, Ge; Yang, Yuefan; Wu, Gang et al. (2016) Early Erythrolysis in the Hematoma After Experimental Intracerebral Hemorrhage. Transl Stroke Res :
Garton, Thomas P; He, Yangdong; Garton, Hugh J L et al. (2016) Hemoglobin-induced neuronal degeneration in the hippocampus after neonatal intraventricular hemorrhage. Brain Res 1635:86-94
Guo, Dewei; Wilkinson, D Andrew; Thompson, B Gregory et al. (2016) MRI Characterization in the Acute Phase of Experimental Subarachnoid Hemorrhage. Transl Stroke Res :
Mao, Shanshan; Xi, Guohua; Keep, Richard F et al. (2016) Role of Lipocalin-2 in Thrombin-Induced Brain Injury. Stroke 47:1078-84
Wan, Shu; Cheng, Yingying; Jin, Hang et al. (2016) Microglia Activation and Polarization After Intracerebral Hemorrhage in Mice: the Role of Protease-Activated Receptor-1. Transl Stroke Res 7:478-487
Ni, Wei; Okauchi, Masanobu; Hatakeyama, Tetsuhiro et al. (2015) Deferoxamine reduces intracerebral hemorrhage-induced white matter damage in aged rats. Exp Neurol 272:128-34
Ni, Wei; Zheng, Mingzhe; Xi, Guohua et al. (2015) Role of lipocalin-2 in brain injury after intracerebral hemorrhage. J Cereb Blood Flow Metab 35:1454-61
Zhao, Hao; Garton, Thomas; Keep, Richard F et al. (2015) Microglia/Macrophage Polarization After Experimental Intracerebral Hemorrhage. Transl Stroke Res 6:407-9

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