Research article summary (published 29 Aug 2009):

Coagulation factor Xa activates thrombin in ischemic neural tissue.

Full Abstract

Thrombin is involved in mediating neuronal death in cerebral ischemia. We investigated its so far unknown mode of activation in ischemic neural tissue. We used an in vitro approach to distinguish the role of circulating coagulation factors from endogenous cerebral mechanisms. We modeled ischemic stroke by subjecting rat organotypic hippocampal slice cultures to 30-min oxygen (5%) and glucose (1 mmol/L) deprivation (OGD). Perinuclear activated factor X (FXa) immunoreactivity was observed in CA1 neurons after OGD. Selective FXa inhibition by fondaparinux during and after OGD significantly reduced neuronal death in the CA1 after 48 h. Thrombin enzyme activity was increased in the medium 24 h after OGD and this increase was prevented by fondaparinux suggesting that FXa catalyzes the conversion of prothrombin to thrombin in neural tissue after ischemia in vitro. Treatment with SCH79797, a selective antagonist of the thrombin receptor protease-activated receptor-1 (PAR-1), significantly decreased neuronal cell death indicating that thrombin signals ischemic damage via PAR-1. The c-Jun N-terminal kinase (JNK) pathway plays an important role in excitotoxicity and cerebral ischemia and we observed activation of the JNK substrate, c-Jun in our model. Both the FXa inhibitor, fondaparinux and the PAR-1 antagonist SCH79797, decreased the level of phospho-c-Jun Ser73. These results indicate that FXa activates thrombin in cerebral ischemia, which leads via PAR-1 to the activation of the JNK pathway resulting in neuronal death.

Author information

Author/s: Thevenet, Jonathan (J); Angelillo-Scherrer, Anne (A); Price, Melanie (M); Hirt, Lorenz (L);

Affiliation: Neurology Laboratory, Neurology Service, CHUV (Centre Hospitalier Universitaire Vaudois) and Lausanne University, Lausanne, Switzerland.

Journal and publication information

Publication Type: In Vitro; Journal Article; Research Support, Non-U.S. Gov't

Journal: Journal of neurochemistry (J Neurochem), published in England. (Language: eng)

Reference: 2009-Nov; vol 111 (issue 3) : pp 828-36

Dates: Created 2009/10/20; Completed 2009/11/06;

PMID: 19719823, status: MEDLINE (last retrieval date: 11/6/2009, IMS Date: )

Sourced from the National Library of Medicine. Abstract text and other information may be subject to copyright.

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MeSH headings (categories)

This article was linked to the MESH Headings shown below.

Animals Animals, Newborn Anoxia - metabolism Anticoagulants - pharmacology Cell Death - drug effects Factor Xa - pharmacology Gene Expression Regulation - drug effects Glucose - deficiency Hippocampus - drug effects; metabolism Ischemia - pathology

JNK Mitogen-Activated Protein Kinases - metabolism Organ Culture Techniques Polysaccharides - pharmacology Pyrroles - pharmacology Quinazolines - pharmacology Rats Receptor, PAR-1 - antagonists & inhibitors Serine - metabolism Signal Transduction - drug effects Thrombin - antagonists & inhibitors; metabolism

Associated Chemicals: Anticoagulants (0) ; N3-cyclopropyl-7-((4-(1-methylethyl)phenyl)methyl)-7H-pyrrolo(3, 2-f)quinazoline-1,3-diamine (0) ; Polysaccharides (0) ; Pyrroles (0) ; Quinazolines (0) ; Receptor, PAR-1 (0) ; fondaparinux (0) ; Glucose (50-99-7) ; Serine (56-45-1) ; JNK Mitogen-Activated Protein Kinases (EC 2.7.1.37) ; Thrombin (EC 3.4.21.5) ; Factor Xa (EC 3.4.21.6)

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