RESUMEN
Oxidative stress critically contributes to the pathogenesis of a variety of neurodegenerative diseases such as multiple sclerosis. Astrocytes are the main regulators of oxidative homeostasis in the brain and dysregulation of these cells likely contributes to the accumulation of oxidative damage. The nuclear factor erythroid 2-related factor 2 (Nrf2) is the main transcriptional regulator of the anti-oxidant stress defense. In this study, we elucidate the effects of astrocytic Nrf2-activation on brain-intrinsic inflammation and lesion development. Cells deficient for the Nrf2 repressor kelch-like ECH-associated protein 1 (Keap1) are characterized by hyperactivation of Nrf2-signaling. Therefore, wild type mice and mice with a GFAP-specific Keap1-deletion were fed with 0.25% cuprizone for 1 or 3 weeks. Cuprizone intoxication induced pronounced oligodendrocyte loss, demyelination and reactive gliosis in wild type animals. In contrast, astrocyte-specific Nrf2-activation was sufficient to prevent oligodendrocyte loss and demyelination, to ameliorate brain intrinsic inflammation and to counteract axonal damage. Our results highlight the potential of the Nrf2/ARE system for the treatment of neuroinflammation in general and of multiple sclerosis in particular. © GLIA 2016;64:2219-2230.
Asunto(s)
Astrocitos/metabolismo , Enfermedades Desmielinizantes/etiología , Regulación de la Expresión Génica/fisiología , Esclerosis Múltiple/complicaciones , Esclerosis Múltiple/patología , Factor 2 Relacionado con NF-E2/metabolismo , Animales , Astrocitos/efectos de los fármacos , Encéfalo/diagnóstico por imagen , Encéfalo/metabolismo , Encéfalo/patología , Quimiocina CXCL10/genética , Quimiocina CXCL10/metabolismo , Cuprizona/toxicidad , Modelos Animales de Enfermedad , Regulación de la Expresión Génica/efectos de los fármacos , Regulación de la Expresión Génica/genética , Proteína Ácida Fibrilar de la Glía/genética , Proteína Ácida Fibrilar de la Glía/metabolismo , Glutamato-Cisteína Ligasa/genética , Glutamato-Cisteína Ligasa/metabolismo , Hemo-Oxigenasa 1/genética , Hemo-Oxigenasa 1/metabolismo , Proteína 1 Asociada A ECH Tipo Kelch/genética , Proteína 1 Asociada A ECH Tipo Kelch/metabolismo , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Inhibidores de la Monoaminooxidasa/toxicidad , Esclerosis Múltiple/inducido químicamente , Factor 2 Relacionado con NF-E2/genética , Estrés Oxidativo/efectos de los fármacos , Estrés Oxidativo/genética , Tiorredoxina Reductasa 1/genética , Tiorredoxina Reductasa 1/metabolismoRESUMEN
OBJECTIVE: The aim of this study was to evaluate the effect of C. zeylanicum aqueous extract on cell growth in the human myelocytic leukemia cell line (THP-1). BACKGROUND: Today, application of Cinnamon for treatment of cancer investigates extensively. Cinnamon has antioxidant, anti-apoptotic and anti-inflammatory properties. METHODS: In this experimental study, THP-1 was incubated in 2, 1, 0.1 and 0.01 mg/ml C. zeylanicum solutions for 24, 48 and 72 hours. Cell cycle was assessed with flow cytometry. Apoptotic cells were identified by Hoechst 33342 staining. Cell proliferation was assessed by the MTT assay. The data were analyzed using descriptive statistics and analytical tests. RESULTS: Samples that supplemented with 0.1 mg/ml C. zeylanicum aqueous extract enhanced induction of apoptosis in THP-1 cell line compared to samples that supplemented with 2, 1 and 0.01 mg/ml. According to flow cytometry analysis, after 24 and 72 hours of incubation in 0.1 and 2 mg/ml C. zeylanicum aqueous extract, respectively, the amount of cells in apoptosis phase was higher than that in the control sample. CONCLUSION: Supplemented C. zeylanicum aqueous extract induced apoptosis in the human myelocytic leukemia cell line (Fig. 4, Ref. 20).
Asunto(s)
Antineoplásicos Fitogénicos/farmacología , Apoptosis/efectos de los fármacos , Cinnamomum zeylanicum , Leucemia Mieloide/tratamiento farmacológico , Leucemia Mieloide/patología , Extractos Vegetales/farmacología , Ciclo Celular/efectos de los fármacos , Línea Celular/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , HumanosRESUMEN
Ischemic stroke is the leading cause of human disability and mortality in the world. Neuroinflammation is the main pathological event following ischemia which contributes to secondary brain tissue damage and is driven by infiltration of circulating immune cells such as macrophages. Because of neuroprotective properties against ischemic brain damage, estrogens have the potential to become of therapeutic interest. However, the exact mechanisms of neuroprotection and signaling pathways is not completely understood. In the current study, 12-week-old male Wistar rats underwent an experimental ischemia by occluding the middle cerebral artery transiently (tMCAO) for 1 h. Male rats subjected to tMCAO were randomly assigned to receive 17ß-estradiol or vehicle treatment. The animals were sacrificed 72 h post tMCAO, transcardially perfused and the brains were proceeded either for TTC staining and gene analysis or for flow cytometry (CD45, CD11b, CD11c, CD40). We found that 17ß-estradiol substitution significantly reduced the cortical infarct which was paralleled by an improved Garcia test scoring. Flow cytometry revealed that CD45+ cells as well as CD45+CD11b+CD11c+ cells were massively increased in tMCAO animals and numbers were nearly restored to sham levels after 17ß-estradiol treatment. Gene expression analysis showed a reperfusion time-dependent upregulation of the markers CD45, CD11b and the activation marker CD40. The reduction in gene expression after 72 h of reperfusion and simultaneous 17ß-estradiol substitution did not reach statistical significance. These data indicate that 17ß-estradiol alleviated the cerebral ischemia-reperfusion injury and selectively suppressed the activation of the neuroinflammatory cascade via reduction of the number of activated microglia or infiltrated monocyte-derived macrophages in brain.