RESUMEN
Demyelination, inflammation, oxidative injury, and glial activation are the main pathological hallmarks of multiple sclerosis (MS). Vitamins, as essential micronutrients, seem to be crucial in the pathogenesis of MS, and particularly vitamins A and C were found to have a protective role in MS development or progression. In this study, the therapeutic potential of combined therapy of vitamins A and C on progression of experimental autoimmune encephalomyelitis (EAE) and myelin repair mechanisms was examined. EAE, an animal model of MS, was induced in female Lewis rats. The rats were treated with daily intraperitoneal injections of vitamins A and C and their combination. We found that co-supplementation of vitamins A and C mitigated neurological severity and EAE disease progression. Histological study confirmed a significant reduction in demyelination size, inflammation and immune cell infiltration as well as microglia and astrocyte activation following co-administration of vitamins A and C. Co-administration of vitamins A and C also decreased the levels of pro-inflammatory cytokines (TNF-α, IL1ß) and iNOS and increased gene expressions of IL-10, Nrf-2, HO-1, and MBP. Combination therapy of vitamins A and C also increased the total antioxidant capacity and decreased levels of oxidative stress markers. Finally, we proved that co-administration of vitamins A and C has anti-apoptotic and neuroprotective impacts in EAE via decreasing caspase-3 and increasing BDNF and NeuN expressing cells. The present study suggests that combined therapy of vitamins A and C may be an effective strategy for development of alternative medicine in boosting myelin repair in demyelinating diseases.
Asunto(s)
Encefalomielitis Autoinmune Experimental , Esclerosis Múltiple , Animales , Ácido Ascórbico/farmacología , Ácido Ascórbico/uso terapéutico , Encefalomielitis Autoinmune Experimental/metabolismo , Femenino , Inflamación/patología , Ratones , Ratones Endogámicos C57BL , Esclerosis Múltiple/tratamiento farmacológico , Ratas , Ratas Endogámicas Lew , Vitamina A/uso terapéutico , Vitaminas/uso terapéuticoRESUMEN
INTRODUCTION: The signaling pathways involved in the antiepileptogenic effect of low frequency electrical stimulation (LFS) have not been fully understood. In the present study the role of extracellular signal-regulated kinase (ERK) signaling cascade was investigated in mediating the inhibitory effects of LFS on kindled seizures. METHODS: Animals received kindling stimulations for seven days (the mean number of stimulation days for achieving stage 5 seizure) according to semi-rapid perforant path kindling protocol (12 stimulations per day at 10â¯min intervals). LFS (0.1â¯ms pulse duration at 1â¯Hz, 800 pulses) was applied at 5â¯min after the last kindling stimulation every day. During the kindling procedure, FR180204 (inhibitor of ERK) was daily microinjected (1⯵g/µl; intracerebroventricular) immediately after the last kindling stimulation and before LFS application. The expression of activated ERK (p-ERK) in the dentate gyrus was also investigated using immunohistochemistry technique. RESULTS: Application of LFS at 5â¯min after the last kindling stimulation had inhibitory effect on kindling rate. FR180204 had no significant effect on seizure parameters when administered at the dose of 1⯵g/µl in kindled group of animals. However, microinjection of FR180204 before LFS application reduced the inhibitory effect of LFS on seizure severity and field potential parameters (i.e. the slope of population field excitatory postsynaptic potentials and population spike amplitude) during kindling. FR180204 also blocked the preventing effects of LFS on kindling-induced increase in early (at 10-40â¯ms intervals) and late (at 300-1000â¯ms intervals) paired pulse depression. In addition, application of LFS following kindling stimulations increased the expression of p-ERK in the dentate gyrus. CONCLUSION: Obtained results showed ERK signaling pathway had important role in mediating the antiepileptogenic effect of LFS in perforant path kindling. These findings represent a promising opportunity to gain insight about LFS mechanism in epilepsy therapy.