Thrombin-Induced Cerebral Hemorrhage: Role of Protease-Activated Receptor-1
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Thrombin-Induced Cerebral Hemorrhage: Role of Protease-Activated Receptor-1 Yingying Cheng & Guohua Xi & Hang Jin & Richard F. Keep & Jiachun Feng & Ya Hua
Received: 14 August 2013 / Revised: 10 September 2013 / Accepted: 11 September 2013 # Springer Science+Business Media New York 2013
Abstract Thrombin causes blood–brain barrier disruption, and this study examined whether thrombin can cause brain hemorrhage through protease-activated receptor-1 (PAR-1). Male wild type and PAR-1 knockout mice had an intracerebral injection of thrombin or saline. Mice then underwent serial T2 magnetic resonance imaging and were euthanized for brain hemoglobin, iron, and interleukin-1β measurements. Thrombin caused massive T2 lesions and brain hemorrhage in wild type mice. These effects were markedly reduced in PAR-1 knockout mice. Thrombin also increased brain interleukin-1β, and this was absent in PAR-1 knockout mice. In conclusion, thrombin increases interleukin-1β levels and induces intracerebral hemorrhage through PAR-1 activation. Keywords Cerebral hemorrhage . Interleukin-1β . Protease-activated receptor-1 (PAR-1) . Thrombin
Introduction Thrombin is a serine protease and contributes to brain injury after both intracerebral hemorrhage and cerebral ischemia [1–4]. Thrombin can be produced in the brain either immediately after a brain hemorrhage or after blood–brain barrier (BBB) disruption. It is well-known that high concentrations of thrombin in the brain are harmful [5]. The effects of thrombin can be nonreceptor-mediated as in, for example, cleavage of fibrinogen to fibrin, or receptorY. Cheng : G. Xi : H. Jin : R. F. Keep : Y. Hua (*) Department of Neurosurgery, University of Michigan, 109 Zina Pitcher Place, Ann Arbor, MI 48109-2200, USA e-mail: [email protected] Y. Cheng : H. Jin : J. Feng Department of Neurology, The First Hospital of Jilin University, Changchun, Jilin, China
mediated as in, for instance, activation of p44/42 mitogenactivated protein kinases [5]. Three protease-activated receptors (PARs), PAR-1, PAR-3, and PAR-4, are thrombin receptors and can be activated by thrombin [6]. Activation of PAR-1 has been linked to many intracellular signaling pathways and is related to brain injury after hemorrhagic and ischemic strokes [7, 8]. Hemorrhagic transformation and hematoma enlargement exacerbate brain damage after ischemic and hemorrhagic strokes. There are many triggers and mediators of hemorrhagic transformation after cerebral ischemia, including the inflammatory mediator, interleukin-1 [9]. Our previous studies have demonstrated that thrombin activity is increased in ischemic and hemorrhagic brain, and thrombin can cause BBB disruption [5]. In the current study, we investigated whether thrombin can cause brain hemorrhage and whether this is through PAR-1. In addition, we also examined the role of PAR-1 in thrombin-induced upregulation of brain interleukin-1β (IL1β), as a potential mediator of vascular disruption.
Materials and Methods Animal Preparation and Intracerebral Infusion The U
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