Intracerebral hemorrhage (ICH) is a common and often fatal subtype of stroke that produces severe neurologic deficits in survivors. Mechanisms of brain injury after intracerebral hemorrhage have been identified during the past decade. Now we know that several processes are responsible for brain injury around the clot. These include coagulation cascade activation with thrombin production, complement cascade activation in the brain parenchyma, and hemoglobin- and iron-induced toxicity. Despite our increased knowledge of ICH-induced injury, there is still no current therapeutic treatment. Estrogen has been shown to be strongly neuroprotective in experimental cerebral ischemia. Our preliminary data show that estrogen reduces brain edema after ICH in mice and in rats. The mechanisms involved in estrogen-induced protection are unknown, a recent study demonstrates that estrogen reduces complement-mediated ischemia-reperfusion injury in heart. Our data lead us to hypothesize that estrogen may also limit complement-mediated brain injury after ICH. To test these hypotheses, we will undertake the following Specific Aims: 1) Determine whether estrogen reduces ICH-induced brain damage;2) Determine whether estrogen can reduce membrane attack complex formation, erythrocyte lysis and iron overload;3) Determine whether estrogen attenuates inflammatory response. Our overall goal is to understand the mechanisms of estrogen-induced neuroprotection after ICH. It is important to understand the mechanisms behind the estrogen-induced protective effects since acute use estrogen could be a new therapy for ICH. It is not possible to directly transpose data on estrogen from cerebral ischemia studies since the mechanisms of brain injury in ICH and cerebral ischemia are different.

Public Health Relevance

Estrogen has been shown to confer strong brain protection in experimental cerebral ischemia. We have found that brain edema is reduced when estrogen is given before or after ICH. The mechanisms involved in estrogen-induced protection are unknown. A recent study demonstrates that estrogen reduces complement-mediated ischemia-reperfusion injury in heart. This study will focuses on the effects of estrogen on complement-mediated brain injury after ICH. It is important to determine the mechanisms underlying the protective effects of estrogen in ICH as the mechanisms of ICH-induced injury differ from ischemia.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS057539-04
Application #
8115940
Study Section
Brain Injury and Neurovascular Pathologies Study Section (BINP)
Program Officer
Koenig, James I
Project Start
2008-08-01
Project End
2014-01-31
Budget Start
2011-08-01
Budget End
2014-01-31
Support Year
4
Fiscal Year
2011
Total Cost
$263,729
Indirect Cost
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
Gao, Feng; Liu, Fuyi; Chen, Zhi et al. (2014) Hydrocephalus after intraventricular hemorrhage: the role of thrombin. J Cereb Blood Flow Metab 34:489-94
Xi, Guohua; Strahle, Jennifer; Hua, Ya et al. (2014) Progress in translational research on intracerebral hemorrhage: is there an end in sight? Prog Neurobiol 115:45-63
Gao, Chao; Du, Hanjian; Hua, Ya et al. (2014) Role of red blood cell lysis and iron in hydrocephalus after intraventricular hemorrhage. J Cereb Blood Flow Metab 34:1070-5
Cheng, Yingying; Xi, Guohua; Jin, Hang et al. (2014) Thrombin-induced cerebral hemorrhage: role of protease-activated receptor-1. Transl Stroke Res 5:472-5
Okubo, Shuichi; Strahle, Jennifer; Keep, Richard F et al. (2013) Subarachnoid hemorrhage-induced hydrocephalus in rats. Stroke 44:547-50
Jin, Hang; Wu, Gang; Hu, Shukun et al. (2013) T2 and T2* magnetic resonance imaging sequences predict brain injury after intracerebral hemorrhage in rats. Acta Neurochir Suppl 118:151-5
Zhang, Chao; Lee, Jin-Yul; Keep, Richard F et al. (2013) Brain edema formation and complement activation in a rat model of subarachnoid hemorrhage. Acta Neurochir Suppl 118:157-61
Karabiyikoglu, Murat; Hua, Ya; Keep, Richard F et al. (2013) Geldanamycin treatment during cerebral ischemia/reperfusion attenuates p44/42 mitogen-activated protein kinase activation and tissue damage. Acta Neurochir Suppl 118:39-43
Dong, Ming; Xi, Guohua; Keep, Richard F et al. (2013) Role of iron in brain lipocalin 2 upregulation after intracerebral hemorrhage in rats. Brain Res 1505:86-92
Okubo, Shuichi; Xi, Guohua; Keep, Richard F et al. (2013) Cerebral hemorrhage, brain edema, and heme oxygenase-1 expression after experimental traumatic brain injury. Acta Neurochir Suppl 118:83-7

Showing the most recent 10 out of 42 publications