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1.
J Neurotrauma ; 35(13): 1481-1494, 2018 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-29316834

RESUMO

Traumatic brain injury (TBI) is induced by immediate physical disruption of brain tissue, and causes death and disability. Studies on experimental TBI animal models show that disruption of the blood-brain barrier (BBB) underlies brain edema and neuroinflammation during the delayed phase of TBI. In neurological disorders, endothelin-1 (ET-1) is involved in BBB dysfunction and brain edema. In this study, the effect of ET antagonists on BBB dysfunction and brain edema were examined in a mouse focal TBI model using lateral fluid percussion injury (FPI). ET-1 and ETB receptors were increased at 2-7 days after FPI, which was accompanied by extravasation of Evans blue (EB) and brain edema. Repeated intracerebroventricular administration of BQ788 (15 nmol/day), an ETB antagonist, from 2 days after FPI promoted recovery of EB extravasation and brain edema, while FR 139317, an ETA antagonist, had no effect. Delayed intravenous administration of BQ788 also promoted recovery from FPI-induced EB extravasation and brain edema. While FPI caused decreases in claudin-5, occludin, and zonula occludens-1 proteins, BQ788 reversed FPI-induced reductions of them. Immunohistochemical observation of the cerebrum after FPI showed that ETB receptors are predominantly expressed in glial fibrillary acidic protein (GFAP)-positive astrocytes. BQ788 reduced FPI-induced increases in GFAP-positive astrocytes. GFAP-positive astrocytes produced vascular endothelial growth factor-A (VEGF-A) and matrix metalloproteinase-9 (MMP9). FPI-induced increases in VEGF-A and MMP-9 production were reversed by BQ788. These results suggest that ETB receptor antagonism during the delayed phase of focal TBI promotes recovery of BBB function and reduction of brain edema.


Assuntos
Barreira Hematoencefálica/efeitos dos fármacos , Edema Encefálico/etiologia , Lesões Encefálicas Traumáticas/complicações , Antagonistas do Receptor de Endotelina B/farmacologia , Oligopeptídeos/farmacologia , Piperidinas/farmacologia , Animais , Edema Encefálico/patologia , Lesões Encefálicas Traumáticas/patologia , Modelos Animais de Doenças , Injeções Intraventriculares , Masculino , Camundongos
2.
Eur J Neurosci ; 42(6): 2356-70, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-26174228

RESUMO

Brain edema is a potentially fatal pathological state that often occurs after brain injuries such as ischemia and trauma. However, therapeutic agents that fundamentally treat brain edema have not yet been established. We previously found that endothelin ETB receptor antagonists attenuate the formation and maintenance of vasogenic brain edema after cold injury in mice. In this study, the effects of ETB antagonists on matrixmetalloproteinase (MMP)9 and vascular endothelial growth factor (VEGF)-A expression were examined in the cold injury model. Cold injury was performed in the left brain of male ddY mice (5-6 weeks old) for the induction of vasogenic edema. Expression of MMP9 and VEGF-A mRNA in the mouse cerebrum was increased by cold injury. Immunohistochemical observations showed that the MMP9 and VEGF-A were mainly produced in reactive astrocytes in the damaged cerebrum. Intracerebroventricular administration of BQ788 (10 µg) or IRL-2500 (10 µg) (selective ETB antagonists) attenuated brain edema and disruption of the blood-brain barrier after cold injury. BQ788 and IRL-2500 reversed the cold injury-induced increases in MMP9 and VEGF-A expression. The induction of reactive astrocytes producing MMP9 and VEGF-A in the damaged cerebrum was attenuated by BQ788 and IRL-2500. These results suggest that attenuations of astrocytic MMP9 and VEGF-A expression by ETB antagonists may be involved in the amelioration of vasogenic brain edema.


Assuntos
Edema Encefálico/metabolismo , Cérebro/metabolismo , Lesão por Frio/metabolismo , Antagonistas do Receptor de Endotelina B/administração & dosagem , Metaloproteinase 9 da Matriz/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo , Animais , Astrócitos/metabolismo , Compostos de Bifenilo/administração & dosagem , Edema Encefálico/prevenção & controle , Cérebro/lesões , Lesão por Frio/prevenção & controle , Dipeptídeos/administração & dosagem , Injeções Intraventriculares , Masculino , Camundongos , Oligopeptídeos/administração & dosagem , Piperidinas/administração & dosagem
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