Thrombin, a serine protease, is an essential component of the coagulation cascade. It is produced immediately in the brain after an intracerebral hemorrhage (ICH) or after the blood- brain barrier breakdown that occurs following many kinds of brain injury. Evidence, both in vivo and in vitro, indicates that high concentrations of thrombin within the brain parenchyma can be deleterious. However, low concentrations of thrombin are neuroprotective. Thus, we have demonstrated that intracerebral pretreatment with a low dose of thrombin (thrombin preconditioning, TPC) reduces brain injury induced by ICH, cerebral ischemia and Parkinson's disease. In order to elucidate the cellular mechanisms involved in TPC-induced neuroprotection we have devised a new rat ICH model. This employs intrahippocampal injection of blood (or blood component). This has the advantage of causing easily quantifiable neuronal loss in contrast to the intracaudate model of ICH in the rat which causes more diffuse injury. Work from our laboratory also suggests that protein synthesis (e.g. iron-handling proteins and heat shock proteins) is essential in thrombin-induced neuroprotection. In this proposal, we will examine the role of thrombin, protease-activated receptor-1 (PAR-1, a thrombin receptor) and the activation of phosphatidylinositol 3 kinase (PI3K)/ ribosomal protein S6 kinases (p70 S6K) and extracellular signal-regulated kinases (ERK)/p70 S6K pathways in mediating protection from neuronal death following ICH. Phosphorylation of p70 S6K is a crucial regulator of protein synthesis. We will test the following two specific aims. 1. To determine whether or not thrombin preconditioning reduces ICH-induced neuronal death through PAR-1 activation. 2. To determine whether or not thrombin-induced neuroprotection results from activation of the PI3K/p70 S6K and ERK/p70 S6K pathways.

Public Health Relevance

The purpose of our project is to investigate the mechanisms involved in TPC. Thrombin- induced brain protection seems to be PAR-1 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. At low concentrations, thrombin protects the brain. Researching how to mediate thrombin will allow us to create new ways to limit brain injury after intracerebral hemorrhage, cerebral ischemia, and Parkinson's disease, and benefit public health.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS039866-09
Application #
7626836
Study Section
Brain Injury and Neurovascular Pathologies Study Section (BINP)
Program Officer
Jacobs, Tom P
Project Start
2000-02-05
Project End
2012-05-31
Budget Start
2009-06-01
Budget End
2010-05-31
Support Year
9
Fiscal Year
2009
Total Cost
$298,340
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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