Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 2 de 2
Filtrar
Más filtros











Base de datos
Intervalo de año de publicación
1.
FASEB J ; 29(5): 1739-53, 2015 May.
Artículo en Inglés | MEDLINE | ID: mdl-25609424

RESUMEN

Impaired blood-brain barrier function represents an important component of hypoxic-ischemic brain injury in the perinatal period. Proinflammatory cytokines could contribute to ischemia-related blood-brain barrier dysfunction. IL-6 increases vascular endothelial cell monolayer permeability in vitro. However, contributions of IL-6 to blood-brain barrier abnormalities have not been examined in the immature brain in vivo. We generated pharmacologic quantities of ovine-specific neutralizing anti-IL-6 mAbs and systemically infused mAbs into fetal sheep at 126 days of gestation after exposure to brain ischemia. Anti-IL-6 mAbs were measured by ELISA in fetal plasma, cerebral cortex, and cerebrospinal fluid, blood-brain barrier permeability was quantified using the blood-to-brain transfer constant in brain regions, and IL-6, tight junction proteins, and plasmalemma vesicle protein (PLVAP) were detected by Western immunoblot. Anti-IL-6 mAb infusions resulted in increases in mAb (P < 0.05) in plasma, brain parenchyma, and cerebrospinal fluid and decreases in brain IL-6 protein. Twenty-four hours after ischemia, anti-IL-6 mAb infusions attenuated ischemia-related increases in blood-brain barrier permeability and modulated tight junction and PLVAP protein expression in fetal brain. We conclude that inhibiting the effects of IL-6 protein with systemic infusions of neutralizing antibodies attenuates ischemia-related increases in blood-brain barrier permeability by inhibiting IL-6 and modulates tight junction proteins after ischemia.


Asunto(s)
Anticuerpos Monoclonales/farmacología , Anticuerpos Neutralizantes/farmacología , Barrera Hematoencefálica/efectos de los fármacos , Isquemia Encefálica/tratamiento farmacológico , Feto/fisiología , Interleucina-6/antagonistas & inhibidores , Daño por Reperfusión/tratamiento farmacológico , Animales , Barrera Hematoencefálica/fisiopatología , Western Blotting , Isquemia Encefálica/fisiopatología , Proteínas Portadoras/metabolismo , Permeabilidad de la Membrana Celular/efectos de los fármacos , Femenino , Feto/efectos de los fármacos , Interleucina-6/inmunología , Interleucina-6/metabolismo , Proteínas de la Membrana/metabolismo , Embarazo , Daño por Reperfusión/fisiopatología , Ovinos , Proteínas de Uniones Estrechas/metabolismo , Uniones Estrechas/efectos de los fármacos , Uniones Estrechas/metabolismo
2.
Neurobiol Dis ; 73: 118-29, 2015 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-25258170

RESUMEN

We have previously shown that increases in blood-brain barrier permeability represent an important component of ischemia-reperfusion related brain injury in the fetus. Pro-inflammatory cytokines could contribute to these abnormalities in blood-brain barrier function. We have generated pharmacological quantities of mouse anti-ovine interleukin-1ß monoclonal antibody and shown that this antibody has very high sensitivity and specificity for interleukin-1ß protein. This antibody also neutralizes the effects of interleukin-1ß protein in vitro. In the current study, we hypothesized that the neutralizing anti-interleukin-1ß monoclonal antibody attenuates ischemia-reperfusion related fetal blood-brain barrier dysfunction. Instrumented ovine fetuses at 127 days of gestation were studied after 30 min of carotid occlusion and 24h of reperfusion. Groups were sham operated placebo-control- (n=5), ischemia-placebo- (n=6), ischemia-anti-IL-1ß antibody- (n=7), and sham-control antibody- (n=2) treated animals. Systemic infusions of placebo (0.154M NaCl) or anti-interleukin-1ß monoclonal antibody (5.1±0.6 mg/kg) were given intravenously to the same sham or ischemic group of fetuses at 15 min and 4h after ischemia. Concentrations of interleukin-1ß protein and anti-interleukin-1ß monoclonal antibody were measured by ELISA in fetal plasma, cerebrospinal fluid, and parietal cerebral cortex. Blood-brain barrier permeability was quantified using the blood-to-brain transfer constant (Ki) with α-aminoisobutyric acid in multiple brain regions. Interleukin-1ß protein was also measured in parietal cerebral cortices and tight junction proteins in multiple brain regions by Western immunoblot. Cerebral cortical interleukin-1ß protein increased (P<0.001) after ischemia-reperfusion. After anti-interleukin-1ß monoclonal antibody infusions, plasma anti-interleukin-1ß monoclonal antibody was elevated (P<0.001), brain anti-interleukin-1ß monoclonal antibody levels were higher (P<0.03), and interleukin-1ß protein concentrations (P<0.03) and protein expressions (P<0.001) were lower in the monoclonal antibody-treated group than in placebo-treated-ischemia-reperfusion group. Monoclonal antibody infusions attenuated ischemia-reperfusion-related increases in Ki across the brain regions (P<0.04), and Ki showed an inverse linear correlation (r= -0.65, P<0.02) with anti-interleukin-1ß monoclonal antibody concentrations in the parietal cortex, but had little effect on tight junction protein expression. We conclude that systemic anti-interleukin-1ß monoclonal antibody infusions after ischemia result in brain anti-interleukin-1ß antibody uptake, and attenuate ischemia-reperfusion-related interleukin-1ß protein up-regulation and increases in blood-brain barrier permeability across brain regions in the fetus. The pro-inflammatory cytokine, interleukin-1ß, contributes to impaired blood-brain barrier function after ischemia in the fetus.


Asunto(s)
Anticuerpos Neutralizantes/uso terapéutico , Barrera Hematoencefálica/efectos de los fármacos , Hipoxia Fetal/tratamiento farmacológico , Hipoxia Fetal/patología , Interleucina-1beta/inmunología , Animales , Anticuerpos Neutralizantes/farmacología , Presión Sanguínea/efectos de los fármacos , Barrera Hematoencefálica/fisiopatología , Encéfalo/embriología , Encéfalo/metabolismo , Permeabilidad Capilar/efectos de los fármacos , Estenosis Carotídea/complicaciones , Citocinas/metabolismo , Modelos Animales de Enfermedad , Embrión de Mamíferos , Ensayo de Inmunoadsorción Enzimática , Femenino , Hipoxia Fetal/etiología , Frecuencia Cardíaca Fetal/efectos de los fármacos , Interleucina-1beta/metabolismo , Ratones , Embarazo , Flujo Sanguíneo Regional/efectos de los fármacos , Ovinos , Proteínas de Uniones Estrechas/metabolismo
SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA