RESUMEN
Sonic hedgehog (SHH) is a morphogen important for neural development during embryogenesis. Recently, beneficial actions of SHH in ischemic injury have been noted. To test whether epidural application of the biolgically active N-terminal fragment of SHH (SHH-N) may reduce the extent of ischemic brain injury, male Long-Evans rats were exposed to a 60-min episode of middle cerebral artery occlusion (MCAO) with topical application of SHH-N and/or its specific inhibitor, cyclopamine, in fibrin glue over the peri-infarct cortex. We found that epidural application of SHH-N substaintially reduced infarct volumes after 7 days of reperfusion, which was reversed by cyclopamine; SHH-N also improved behavioral outcomes as assessed by global neurological functions, rotarod test, and grasping power test. Furthermore, SHH-N attenuated the extents of protein oxidation, lipid peroxidation, and apoptosis induced by focal ischemia/reperfusion. Immunohistochemical staining coupled with bromodeoxyuridine (BrdU) incorporation revealed that SHH-N enhanced post-ischemic angiogenesis, stimulated the proliferation of nestin-positive (nestin(+)) neural progenitor cells (NPCs), and suppressed astrocytosis. Our results thus revealed multifaceted protective mechanisms of SHH-N against focal cerebral ischemia/reperfusion.
Asunto(s)
Antioxidantes/uso terapéutico , Apoptosis/efectos de los fármacos , Proteínas Hedgehog/uso terapéutico , Infarto de la Arteria Cerebral Media/tratamiento farmacológico , Neovascularización Patológica/prevención & control , Animales , Antioxidantes/química , Bromodesoxiuridina , Proliferación Celular/efectos de los fármacos , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Fuerza de la Mano/fisiología , Proteínas Hedgehog/química , Etiquetado Corte-Fin in Situ , Infarto de la Arteria Cerebral Media/complicaciones , Infarto de la Arteria Cerebral Media/patología , Peroxidación de Lípido/efectos de los fármacos , Masculino , Actividad Motora/efectos de los fármacos , Neovascularización Patológica/etiología , Nestina/metabolismo , Células-Madre Neurales/efectos de los fármacos , Examen Neurológico , Oxidación-Reducción/efectos de los fármacos , Ratas , Ratas Long-Evans , Prueba de Desempeño de Rotación con Aceleración Constante , Alcaloides de Veratrum/uso terapéuticoRESUMEN
The purpose of this study was to investigate the effect of resveratrol, a polyphenol present in grapes and red wine, on ventricular remodeling after myocardial infarction (MI) in rats. After permanent ligation of the left anterior descending artery, surviving rats were randomly allocated to three groups and treated with 1 mg/kg/day resveratrol (R-1 group), 0.1 mg/kg/day resveratrol (R-0.1 group), or vehicles (control group) administered by intraperitoneal injection once daily for four weeks. We examined the effects of resveratrol by echocardiography, hemodynamic studies, histologic examinations, and real-time quantitative polymerase chain reaction. The R-1 group had significantly increased fractional shortening of the left ventricle, ameliorated left ventricular dilatation, reduced left ventricular end-diastolic pressure, and reduced infarct size. In contrast, the R-0.1 group experienced no beneficial effects on myocardial infarction. The R-1 group also had significantly attenuated expression of myocardial atrial natriuretic peptide and transforming growth factor-beta1 mRNAs. This study indicates that resveratrol is a potent cardioprotective agent in MI rats. Its cardioprotective effects may be due to a reduction of atrial natriuretic peptide and transforming growth factor-beta1, which are known to protect the heart from detrimental remodeling.
Asunto(s)
Antioxidantes/farmacología , Isquemia Miocárdica , Estilbenos/farmacología , Remodelación Ventricular/efectos de los fármacos , Animales , Factor Natriurético Atrial/genética , Factor Natriurético Atrial/metabolismo , Colágeno Tipo I/genética , Colágeno Tipo I/metabolismo , Ecocardiografía , Hemodinámica , Masculino , Ratones , Isquemia Miocárdica/metabolismo , Isquemia Miocárdica/patología , Distribución Aleatoria , Ratas , Ratas Sprague-Dawley , Resveratrol , Factor de Crecimiento Transformador beta1/genética , Factor de Crecimiento Transformador beta1/metabolismoRESUMEN
BACKGROUND: Our prior study showed that resveratrol could suppress infarct volume and exert neuroprotective effect on rats subjected to focal cerebral ischemia (FCI) injury. Recently, it has been reported in some literature that resveratrol protects the spinal cord, kidney, and heart from ischemia-reperfusion injury through upregulation of nitric oxide (NO). Therefore, this study was designed to investigate the role of nitric oxide on the neuroprotective mechanisms of resveratrol on rats after FCI injury. METHODS: The FCI injury was induced by the middle cerebral artery (MCA) occlusion for 1 hour and then a 24-hour reperfusion followed in the anesthetized Long-Evans rats. Resveratrol was intravenously injected after 1 hour MCA occlusion. RESULTS: Treatment of resveratrol (0.1 and 1 microg/kg) decreased the lactate dehydrogenase (LDH) in plasma and malondialdehyde (MDA) in FCI injury brain tissue, whereas the level of NO in plasma was increased. In addition, resveratrol downregulated protein and mRNA expression of inducible nitric oxide synthase (iNOS), and upregulated protein and mRNA expression of endothelial nitric oxide synthase (eNOS), while the expression of protein and mRNA of neuronal nitric oxide synthase (nNOS) was unchanged. Pretreatment with N(G)-nitro-L-arginine methyl ester (L-NAME, the nonselective NOS inhibitor) or L-N(5)-(1-iminoethyl)-ornithine (L-NIO, the eNOS selective inhibitor) completely blocked the effect of resveratrol in decreasing infarction volumes. CONCLUSIONS: This study demonstrated the important role of NO in the neuroprotective effect of resveratrol in FCI injury.