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      Treating seizures and epilepsy with anticoagulants?

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          Abstract

          Thrombin is a serine protease playing an essential role in the blood coagulation cascade. Recent work, however, has identified a novel role for thrombin-mediated signaling pathways in the central nervous system. Binding of thrombin to protease-activated receptors (PARs) in the brain appears to have multiple actions affecting both health and disease. Specifically, thrombin has been shown to lead to the onset of seizures via PAR-1 activation. In this perspective article, we review the putative mechanisms by which thrombin causes seizures and epilepsy. We propose a potential role of PAR-1 antagonists and novel thrombin inhibitors as new, possible antiepileptic drugs.

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          Most cited references 57

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          The blood-brain barrier: an overview: structure, regulation, and clinical implications.

          The blood-brain barrier (BBB) is a diffusion barrier, which impedes influx of most compounds from blood to brain. Three cellular elements of the brain microvasculature compose the BBB-endothelial cells, astrocyte end-feet, and pericytes (PCs). Tight junctions (TJs), present between the cerebral endothelial cells, form a diffusion barrier, which selectively excludes most blood-borne substances from entering the brain. Astrocytic end-feet tightly ensheath the vessel wall and appear to be critical for the induction and maintenance of the TJ barrier, but astrocytes are not believed to have a barrier function in the mammalian brain. Dysfunction of the BBB, for example, impairment of the TJ seal, complicates a number of neurologic diseases including stroke and neuroinflammatory disorders. We review here the recent developments in our understanding of the BBB and the role of the BBB dysfunction in CNS disease. We have focused on intraventricular hemorrhage (IVH) in premature infants, which may involve dysfunction of the TJ seal as well as immaturity of the BBB in the germinal matrix (GM). A paucity of TJs or PCs, coupled with incomplete coverage of blood vessels by astrocyte end-feet, may account for the fragility of blood vessels in the GM of premature infants. Finally, this review describes the pathogenesis of increased BBB permeability in hypoxia-ischemia and inflammatory mechanisms involving the BBB in septic encephalopathy, HIV-induced dementia, multiple sclerosis, and Alzheimer disease.
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            Thrombin signalling and protease-activated receptors.

            How does the coagulation protease thrombin regulate cellular behaviour? The protease-activated receptors (PARs) provide one answer. In concert with the coagulation cascade, these receptors provide an elegant mechanism linking mechanical information in the form of tissue injury or vascular leakage to cellular responses. Roles for PARs are beginning to emerge in haemostasis and thrombosis, inflammation, and perhaps even blood vessel development.
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              Mechanisms of brain injury after intracerebral haemorrhage.

              The past decade has resulted in a rapid increase in knowledge of mechanisms underlying brain injury induced by intracerebral haemorrhage (ICH). Animal studies have suggested roles for clot-derived factors and the initial physical trauma and mass effect as a result of haemorrhage. The coagulation cascade (especially thrombin), haemoglobin breakdown products, and inflammation all play a part in ICH-induced injury and could provide new therapeutic targets. Human imaging has shown that many ICH continue to expand after the initial ictus. Rebleeding soon after the initial haemorrhage is common and forms the basis of a current clinical trial using factor VIIa to prevent rebleeding. However, questions about mechanisms of injuries remain. There are conflicting data on the role of ischaemia in ICH and there is uncertainty over the role of clot removal in ICH therapy. The next decade should bring further information about the underlying mechanisms of ICH-induced brain injury and new therapeutic interventions for this severe form of stroke. This review addresses our current understanding of the mechanisms underlying ICH-induced brain injury.
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                Author and article information

                Journal
                Front Cell Neurosci
                Front Cell Neurosci
                Front. Cell. Neurosci.
                Frontiers in Cellular Neuroscience
                Frontiers Media S.A.
                1662-5102
                05 March 2013
                2013
                : 7
                Affiliations
                1Talpiot Medical Leadership Program, The Chaim Sheba Medical Center Tel HaShomer, Israel
                2Department of Neurology, The J. Sagol Neuroscience Center, The Chaim Sheba Medical Center Tel HaShomer, Israel
                3 Department of Neurology, Sackler Faculty of Medicine, Tel Aviv University Tel Aviv, Israel
                4Institute of Clinical Neuroanatomy, Neuroscience Center, Goethe-University Frankfurt Frankfurt/Main, Germany
                5Department of Neurobiology, The Weizmann Institute of Science Rehovot, Israel
                Author notes

                Edited by: Enrico Cherubini, International School for Advanced Studies, Italy

                Reviewed by: Andrea Nistri, Scuola Internazionale Superiore di Studi Avanzati, Italy; Giuliano Avanzini, Fondazione IRCCS Istituto Neurologico Carlo Besta, Italy

                *Correspondence: Nicola Maggio, Department of Neurology, The J. Sagol Neuroscience Center, The Chaim Sheba Medical Center, 52621 Tel HaShomer, Israel. e-mail: nicola.maggio@ 123456sheba.health. gov.il
                Article
                10.3389/fncel.2013.00019
                3587848
                23467310
                Copyright © Maggio, Blatt, Vlachos, Tanne, Chapman and Segal

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in other forums, provided the original authors and source are credited and subject to any copyright notices concerning any third-party graphics etc.

                Page count
                Figures: 2, Tables: 0, Equations: 0, References: 57, Pages: 5, Words: 0
                Categories
                Neuroscience
                Perspective Article

                Neurosciences

                thrombin, par-1, seizures, blood–brain barrier, novel anticoagulants

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