Spontaneous intracerebral hemorrhage (ICH) is a common and often fatal stroke subtype. If the patient survives the ictus, the resulting hematoma within brain parenchyma triggers a series of events leading to secondary insults and severe neurological deficits. Although the hematoma in human gradually resolves within several months, restoration of function is graded and usually incomplete. The neurological deficits in ICH patients are permanent and disabling. Iron overload and oxidative stress contribute to brain damage after ICH. Both iron chelators and free radical scavengers can reduce ICH-induced brain injury in animals. Minocycline, a second-generation tetracycline-based molecule, is a potent inhibitor of microglia activation. It is a highly lipophilic compound and penetrates the brain-blood barrier easily. Minocycline can chelate iron and a recent study has shown that minocycline attenuates iron neurotoxicity in cortical neuronal culture by chelating iron. In our preliminary study, we also have demonstrated: 1) Brain iron overload occurs in a rat model of ICH and minocycline reduces brain non-heme iron levels following ICH; 2) Coinjection of minocycline rather than macrophage/microglia inhibitory factor with iron abolishes iron-induced brain edema in young rats; 3) Minocycline reduces brain edema, brain atrophy and neurological deficits after ICH in young rats; 4) Levels of serum total iron are increased after ICH, which is reduced by systemic use of minocycline. However, major gaps in our knowledge regarding minocycline and ICH need to be filled. For example, it is not clear whether minocycline attenuates ICH-induced iron overload and brain injury in a dose dependent manner, whether minocycline can reduce brain injury in aged ICH animals (ICH is primarily a disease of the elderly), and whether minocycline reduces white matter damage after ICH. In this application, therefore, we propose to test the following Specific Aims: 1) To determine whether minocycline acts as a combination therapy reducing ICH-induced brain injury via iron chelation and microglial inhibition in aged rats; 2) To determine whether minocycline reduces brain iron overload and brain injury after intracerebral hemorrhage in aged rats; 3) To determine whether minocycline reduces ICH-induced brain iron overload and brain damage in pigs. Data from the proposed studies are very useful for developing a minocycline-ICH trial. The purpose of our project is to determine whether minocycline reduces brain iron overload and ICH-induced brain damage in aged rats and pigs. The long-term goal of our studies is to limit hemorrhagic brain damage in patients.

Public Health Relevance

After a cerebral hemorrhage, lysis of red blood cells causes a buildup of iron in the brain. Brain iron accumulation can cause brain cell death and neurological deficits. Our recent studies found that minocycline reduces brain iron levels and improves functional outcome in a rat model of cerebral hemorrhage. The purpose of this project is to investigate iron, minocycline and brain injury after cerebral hemorrhage. The long-term goal of our studies is to limit brain injury after cerebral hemorrhage.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
1R01NS090925-01A1
Application #
8967289
Study Section
Special Emphasis Panel (ZRG1-BDCN-K (02))
Program Officer
Koenig, James I
Project Start
2015-05-01
Project End
2020-03-30
Budget Start
2015-05-01
Budget End
2016-03-31
Support Year
1
Fiscal Year
2015
Total Cost
$339,154
Indirect Cost
$120,404
Name
University of Michigan Ann Arbor
Department
Neurosurgery
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
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