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Corticosteroid therapy is employed in multiple sclerosis (MS), a neurological abnormality characterized by an inflammatory process. Melatonin, a potent sleep-promoting and circadian phase regulatory hormone, is produced mainly in the pineal gland whose inhibition leads to sleep disturbances.In this study, methylprednisolone (MP) corticosteroid treatment was used in an acute experimental autoimmune encephalomyelitis (EAE) rat model (intraperitoneal, 30 mg/kg) and in MS patients (intravenous, 1000 mg/day), followed by assessing melatonin serum levels.Results showed that mean clinical scores were significantly improved in MP- versus PBS-treated EAE rats (1.5 vs 4.1, respectively). In addition, MP was found to induce a significant decrease in serum IFN-γ, whereas IL-4 levels were significantly increased, in comparison to PBS-treated EAE rats. The ratio of IFN-γ/IL-4, which acts as an indicator of Th-1/Th-2, was significantly lower in MP treated, compared to PBS treated EAE rats or controls. Moreover, serum levels of melatonin showed a significant decrease in the MP group, compared to normal rats. Moreover, MP therapy for 1 or 2 days resulted in a significant reduction of melatonin serum levels in MS patients.Since corticosteroids cause a reduction in melatonin serum levels, an important hormone in sleep regulation, their prescription to MS patients should be carefully considered. Corticosteroids could be a cause of insomnia and sleep disturbance in patients receiving this type of medication.Serum melatonin decreases in EAE animal model of MS, compared to controls.Methylprednisolone (MP) corticosteroid therapy attenuates MS severity in EAE model.MP therapy exacerbates the reduction of melatonin in EAE model and MS patients.Corticosteroids therapy could affect melatonin role in sleep quality.