Intraventricular hemorrhage (IVH) occurs in many patients with intracerebral and subarachnoid hemorrhage (SAH). Recent studies have found IVH is a predictor of poor outcome after intracerebral hemorrhage and that hydrocephalus develops in 55% intracerebral hemorrhage patients with IVH. Hydrocephalus is also a major problem in SAH. Early hydrocephalus occurs in 20-50% SAH patients and is associated with poor clinical grade. However, the mechanisms of IVH-induced hydrocephalus are not well understood. Lysis of erythrocytes results in iron accumulation in the brain and causes brain damage after intracerebral hemorrhage. However, the role of erythrocyte lysis and iron toxicity in IVH-induced brain injury and hydrocephalus has still to be elucidated. Erythrocyte lysis after IVH may start very early. Hemoglobin released from red blood cells reaches its peak concentration by the second day following injection of blood into the cerebrospinal fluid of dogs. Hemoglobin release, from lysis of erythrocytes in human intracranial hemorrhage, increases during the first few days. Erythrocyte lysis appears to result from either depletion of intracellulr energy reserves or activation of the complement system. We have established an IVH model in rats and long-term ventricular dilatation has been observed. Recently we have found that hydrocephalus occurs in a model of SAH which results in intraventricular blood. Our preliminary data have demonstrated: 1) Intraventricular injection of autologous whole blood causes iron accumulation, hydrocephalus, neuronal death and brain tissue loss in the hippocampus;2) Intraventricular injection of lysed erythrocytes rather than packed erythrocytes causes hydrocephalus by 24 hours;3) Heme oxygenase-1 and ferritin levels are increased significantly in the hippocampus and periventricular areas following IVH;4) Intraventricular injection of iron alone can also result in acute hydrocephalus;5) Deferoxamine, an iron chelator, reduces IVH-induced hydrocephalus and hippocampal tissue loss. In this application, we propose to test the following specific aims: 1) Determine whether erythrocyte lysis and hemoglobin release cause hydrocephalus and neuronal death following IVH;2) Determine whether complement inhibition reduces erythrocyte lysis and IVH/SAH-induced brain injury;3) Examine the natural time courses of iron buildup, oxidative stress and upregulation of iron handling proteins in the brain after IVH;4) Determine whether heme oxygenase inhibition reduces heme degradation and IVH/SAH-induced brain injury;and 5) Determine whether iron chelation reduces oxidative stress, hydrocephalus and neuronal death after IVH/SAH in aged rats. The purpose of our project is to investigate the mechanisms of brain injury after IVH. The long-term goal of our studies is to limit hemorrhagic brain damage in patients.

Public Health Relevance

Bleeding into the fluid cavities within the brain (intraventricular hemorrhage) occurs in many patients with cerebral hemorrhage and subarachnoid hemorrhage. It often causes hydrocephalus and it is a predictor of poor outcome in patients with cerebral hemorrhage. The mechanisms of brain injury and hydrocephalus induction after intraventricular hemorrhage are not well understood, but we have recently found that lysis of red blood cells with iron release may be involved. The purpose of this project is to investigate those mechanisms. The long-term goal of our studies is to reduce brain injury after intraventricular hemorrhage.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS073595-03
Application #
8606266
Study Section
Brain Injury and Neurovascular Pathologies Study Section (BINP)
Program Officer
Koenig, James I
Project Start
2012-02-15
Project End
2017-01-31
Budget Start
2014-02-01
Budget End
2015-01-31
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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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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