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Investigation of the role of the serine protease thrombin in cerebral ischemia

English title Investigation of the role of the serine protease thrombin in cerebral ischemia
Applicant Hirt Lorenz
Number 112484
Funding scheme Project funding
Research institution Service de Neurologie Département des Neurosciences Cliniques CHUV
Institution of higher education University of Lausanne - LA
Main discipline Neurophysiology and Brain Research
Start/End 01.01.2007 - 31.12.2009
Approved amount 228'729.00
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Keywords (6)

cerebral ischemia; preconditioning; thrombin; protease nexin 1; neuroprotection; c-Jun-terminal kinase

Lay Summary (English)

Lay summary
Investigation of the role of the serine protease thrombin in cerebral ischemia
Neuroprotection, defined as a strategy to protect cerebral tissue after an insult, has been successfully achieved in experimental ischemia. In human stroke, the only available treatment of the acute phase is thrombolysis which can be administered to a limited number of patients. There is a strong need to develop potent neuroprotective strategies. Ischemic preconditioning, induced by a brief sublethal ischemic episode results in ischemic tolerance, namely an increased resistance to subsequent more severe ischemic events. In the brain, an ischemia of low intensity can induce protection against a more severe cerebral ischemia, although the mechanisms of this preconditioning are not as well described as in the heart. While high doses of the serine protease thrombin cause cell death, preconditioning can result from exposure to a low dose of thrombin.Preconditioning doses attenuate brain oedema induced by the subsequent administration of a higher dose of thrombin, or can attenuate tissue damage caused by a subsequent severe ischemia. We have shown that thrombin preconditioning requires the c-jun-N-terminal kinase (JNK), which also plays a major role in ischemic neuronal death. Furthermore, thrombin appears to mediate ischemic neuronal death. Understanding the mechanisms of ischemic and thrombin preconditioning should lead to new therapeutic approaches in the protection against cerebral ischemia and ischemia associated cerebral oedema.
The aim of this project is to analyse the dual role of the serine protease thrombin in cell death and survival in the brain. This signalling molecule, like JNK, appears to have opposing roles depending on the concentration, time and place of activation.
Both in vivo and in vitro models of ischemia are available in ourlaboratory: A model of transient middle cerebral artery occlusion in the mouse and a model of oxygen and glucose deprivation (OGD) on organotypic cultures of rat and mouse hippocampal slices. We have established models of ischemic tolerance in both models. Using specific inhibitors, we have, on the one hand, developed several neuroprotection strategies, and on the other were able to block the induction of tolerance.(1-3)
Preconditioning leads to profound neuroprotection. Delineating the underlying mechanisms of protection within the neural cells should lead to the identification of key proteins and pathways which could be therapeutic targets for neuroprotection after cerebral ischemia. The project will define more precisely the role of the coagulation factor thrombin in the brain. It will also help to gain insights into the dual role of signalling molecules in cell survival and death, one of the current challenges in biology.

1. T. Borsello et al., Nat. Med. 9, 1180 (2003).
2. L. Hirt et al., Stroke 35, 1738 (2004).
3. R. M. de Castro et al., Exp. Neurol. 198, 199 (2006).

Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants


Associated projects

Number Title Start Funding scheme
135617 Imaging neuroinflammatory reactions in cerebral ischemia: role of thrombin 01.03.2012 Project funding
68306 Ischemic brain injury: molecular mechanisms for protection and prevention. 01.11.2002 Project funding