RESUMEN
The therapeutic potential of glatiramer acetate (GA) in Multiple Sclerosis has been apparent for many years and has been proven effective in experimental allergic encephalomyelitis, one of its animal models. The cuprizone (CPZ) model for the CNS de/remyelination has gained a renewed interest during the past decade. CPZ-induced demyelination is considered to be primarily an oligodendrocyte loss with participation of the inflammatory response. As the blood brain barrier remains intact, we found this model advantageous for studying GA effects on CNS remyelination with minimum influence of the peripheral immune cellular component. Our results show that GA, given one week before the CPZ treatment, had a maturational effect functional to remyelination. However, myelin was unorganized as compared to controls. When GA was concomitantly injected with CPZ, oligodendroglial precursor proliferation diminished in favor of maturation and myelin recovered an organized disposition. GA-treated animals also show microglial cell (MG) activation. In vitro assays demonstrated that GA-primed MG cultures had a significant increase in IL-10 and IL-4 secretion. GA-challenged MG-conditioned media induced oligodendrocyte proliferation and subsequent differentiation. Our results suggest that, in addition to its well-recognized immunoregulatory properties, GA also has an effect on resident immuno-response, which leads mature oligodendrocytes towards CPZ-induced demyelination repair.
Asunto(s)
Cuprizona/toxicidad , Enfermedades Desmielinizantes/inducido químicamente , Oligodendroglía/efectos de los fármacos , Péptidos/farmacología , Animales , Células Cultivadas , Acetato de Glatiramer , Microscopía Electrónica , Oligodendroglía/citología , Ratas , Ratas WistarRESUMEN
In rats, iron deficiency produces an alteration in myelin formation. However, there is limited information on the effects of this condition on oligodendroglial cell (OLGc) proliferation and maturation. In the present study, we further analyzed the hypomyelination associated with iron deficiency by studying the dynamics of oligodendrogenesis. Rats were fed control (40 mg Fe/kg) or iron-deficient (4 mg Fe/kg) diets from gestation day 5 until postnatal day 3 (P3) or 11 (P11). OLGc proliferation, migration and differentiation were investigated before and after an intracranial injection of apotransferrin at 3 days of age (P3). The proliferating cell population was evaluated at P3. Iron-deficient (ID) animals showed an increase in the oligodendrocyte precursors cell (OPC) population in comparison with controls. The overall pattern of migration of cells labeled with BrdU was investigated at P11. Iron deficiency increased the amount of BrdU(+) cells in the corpus callosum (CC) and decreased OLGc maturation and myelin formation. Changes in nerve conduction were analyzed by measuring visual evoked potentials. Latency and amplitude were significantly disturbed in ID rats compared with controls. Both parameters were substantially normalized when animals were treated with a single intracranial injection of 350 ng apotransferrin (aTf). The current results give support to the idea that iron deficiency increases the number of proliferating and undifferentiated cells in the CC compared with the control. Treatment with aTf almost completely reverted the effects of iron deficiency, both changing the migration pattern and increasing the number of mature cells in the CC and myelin formation.
Asunto(s)
Apoproteínas/uso terapéutico , Proliferación Celular/efectos de los fármacos , Enfermedades Desmielinizantes/tratamiento farmacológico , Enfermedades Desmielinizantes/patología , Deficiencias de Hierro , Oligodendroglía/efectos de los fármacos , Efectos Tardíos de la Exposición Prenatal , Transferrina/uso terapéutico , Factores de Edad , Análisis de Varianza , Animales , Animales Recién Nacidos , Apoproteínas/metabolismo , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Peso Corporal/fisiología , Encéfalo , Bromodesoxiuridina/metabolismo , Recuento de Células , Diferenciación Celular/efectos de los fármacos , Diferenciación Celular/fisiología , Cuerpo Calloso/metabolismo , Cuerpo Calloso/patología , Enfermedades Desmielinizantes/etiología , Enfermedades Desmielinizantes/fisiopatología , Electroencefalografía/métodos , Potenciales Evocados Visuales/efectos de los fármacos , Potenciales Evocados Visuales/fisiología , Femenino , Regulación del Desarrollo de la Expresión Génica/efectos de los fármacos , Regulación del Desarrollo de la Expresión Génica/fisiología , Hematócrito/métodos , Proteína Básica de Mielina/metabolismo , Proteínas del Tejido Nervioso/metabolismo , Molécula L1 de Adhesión de Célula Nerviosa/metabolismo , Oligodendroglía/fisiología , Estimulación Luminosa/métodos , Embarazo , Antígeno Nuclear de Célula en Proliferación/metabolismo , Ratas , Ácidos Siálicos/metabolismo , Transferrina/metabolismoRESUMEN
We have used a model of iron deficiency in the rat to analyze the effects of a disruption in iron availability on oligodendroglial cell (OLGc) maturation and myelinogenesis and to explore the possible beneficial influence of an intracranial injection (ICI) of apotransferrin (aTf) at 3 days of age on this process. Studies carried out on postnatal days 17 and 24 showed that iron deficiency produced a decrease in myelin proteins and lipids at 24 days of age. Immunohistochemistry showed that in untreated iron-deficient (ID) rats, the immunoreactivity of anti-adenomatous polyposis coli (APC) and anti-MBP antibodies decreased markedly with reference to normal controls, whereas in ID rats treated with an ICI of aTf, the immunoreactivity of these markers increased. A similar situation occurred with the immunoreactivity of H-ferritin. In primary OLGc cultures from ID rats, there was a high number of cells positive to the antibody against the polysialylated form of the cell surface glycoprotein NCAM (PSA-NCAM) compared with in OLGc cultures prepared from normal controls or from ID animals treated with aTf. The number of MBP+ cells in cultures from ID rats increased after treatment with aTf. The presence of lipid rafts evaluated with a specific anti-protein prion cellular (PrPc) antibody showed a smaller number of PrPc-positive structures in ID rat cultures. Treatment of the ID animals with a single ICI of aTf stimulated myelination, producing a significant correction in the different biochemical parameters affected by ID.