Intracerebral hemorrhage (ICH) is a common and often fatal subtype of stroke and produces severe neurologic deficits in survivors. Brain injury after ICH appears to involve several phases. These include an early phase involving the clotting cascade and thrombin production and a later phase involving erythrocyte lysis and hemoglobin toxicity. Although high concentrations of thrombin cause brain edema and cell death, low concentrations are neuroprotective. Thus, we have found that prior treatment with a low dose of thrombin attenuates the brain edema induced by thrombin or hemorrhage, and significantly reduces the infarct size in a rat middle cerebral artery occlusion model. We have termed this phenomenon thrombin preconditioning (TPC). In our recent studies, we have found that TPC not only reduces brain edema induced by high dose thrombin, but also attenuates edema induced by lysed erythrocytes and FeCl[2]. TPC appear to involve activation of thrombin receptor, HIF-1alpha upregulation and increased transferrin, transferrin receptor and ferritin levels. This suggests that thrombin release during an ICH might induce protective mechanisms against factors released upon clot lysis. This data has led us to the following Specific Aims: 1) To determine whether TPC reduces hemorrhagic brain injury caused by lysis of erythrocytes. 2) To determine whether protease-activated receptors (PARs) play a key role in TPC. 3) To determine whether TPC modulates iron transport and storage protein levels in the brain, which then affects iron homeostasis after ICH. The purpose of our project is to investigate the mechanisms involved in TPC. An examination of TPC will also help our understanding of ischemic preconditioning since preliminary data suggests that TPC is a component of that phenomenon. It should be noted that TPC seems to be receptor mediated, greatly facilitating analysis compared to ischemic preconditioning. The long-term goal of these studies is to find mechanisms that can be used to limit brain injury after ICH.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
2R01NS039866-04
Application #
6609468
Study Section
Special Emphasis Panel (ZRG1-BDCN-3 (01))
Project Start
2000-02-05
Project End
2007-01-31
Budget Start
2003-02-01
Budget End
2004-01-31
Support Year
4
Fiscal Year
2003
Total Cost
$252,623
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
Jin, Hang; Xi, Guohua; Keep, Richard F et al. (2013) DARPP-32 to quantify intracerebral hemorrhage-induced neuronal death in basal ganglia. Transl Stroke Res 4:130-134
Xie, Qing; Xi, Guohua; Gong, Ye et al. (2013) Protease activated receptor-1 and brain edema formation in glioma models. Acta Neurochir Suppl 118:191-4
Okubo, Shuichi; Strahle, Jennifer; Keep, Richard F et al. (2013) Subarachnoid hemorrhage-induced hydrocephalus in rats. Stroke 44:547-50
He, Yangdong; Liu, Wenquan; Koch, Lauren G et al. (2013) Susceptibility to intracerebral hemorrhage-induced brain injury segregates with low aerobic capacity in rats. Neurobiol Dis 49:22-8
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
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
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
Wang, Michael M; Xi, Guohua; Keep, Richard F (2013) Should the STAIR criteria be modified for preconditioning studies? Transl Stroke Res 4:3-14

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