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Exp Neurol ; 217(1): 136-46, 2009 May.
Artículo en Inglés | MEDLINE | ID: mdl-19416668

RESUMEN

Protease-activated receptor 1 (PAR1) is a G-protein coupled receptor that is expressed throughout the central nervous system. PAR1 activation by brain-derived as well as blood-derived proteases has been shown to have variable and complex effects in a variety of animal models of neuronal injury and inflammation. In this study, we have evaluated the effects of PAR1 on lesion volume in wild-type or PAR1-/- C57Bl/6 mice subjected to transient occlusion of the middle cerebral artery or injected with NMDA in the striatum. We found that removal of PAR1 reduced infarct volume following transient focal ischemia to 57% of control. Removal of PAR1 or application of a PAR1 antagonist also reduced the neuronal injury associated with intrastriatal injection of NMDA to 60% of control. To explore whether NMDA receptor potentiation by PAR1 activation contributes to the harmful effects of PAR1, we investigated the effect of NMDA receptor antagonists on the neuroprotective phenotype of PAR1-/- mice. We found that MK801 reduced penumbral but not core neuronal injury in mice subjected to transient middle cerebral artery occlusion or intrastriatal NMDA injection. Lesion volumes in both models were not significantly different between PAR1-/- mice treated with and without MK801. Use of the NMDA receptor antagonist and dissociative anesthetic ketamine also renders NMDA-induced lesion volumes identical in PAR1-/- mice and wild-type mice. These data suggest that the ability of PAR1 activation to potentiate NMDA receptor function may underlie its harmful actions during injury.


Asunto(s)
Lesiones Encefálicas/prevención & control , Neuronas/fisiología , Receptor PAR-1/fisiología , Receptores de N-Metil-D-Aspartato/fisiología , Análisis de Varianza , Animales , Lesiones Encefálicas/genética , Lesiones Encefálicas/metabolismo , Lesiones Encefálicas/patología , Células Cultivadas , Cuerpo Estriado/citología , Cuerpo Estriado/efectos de los fármacos , Cuerpo Estriado/metabolismo , Modelos Animales de Enfermedad , Maleato de Dizocilpina/farmacología , Embrión de Mamíferos , Agonistas de Aminoácidos Excitadores/farmacología , Agonistas de Aminoácidos Excitadores/uso terapéutico , Antagonistas de Aminoácidos Excitadores/farmacología , Femenino , Guanidinas/farmacología , Inyecciones Intraventriculares/métodos , Ataque Isquémico Transitorio/genética , Ataque Isquémico Transitorio/prevención & control , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , N-Metilaspartato/farmacología , N-Metilaspartato/uso terapéutico , Neuronas/efectos de los fármacos , Oligopéptidos/farmacología , Embarazo , Ratas , Receptor PAR-1/antagonistas & inhibidores , Receptor PAR-1/deficiencia , Receptor PAR-1/metabolismo
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