Valproic Acid Attenuates Disease Symptoms and Increases Endogenous Myelin Repair by Recruiting Neural Stem Cells and Oligodendrocyte Progenitors in Experimental Autoimmune Encephalomyelitis

摘要

Background: Inefficient remyelination of demyelinated plaques in multiple sclerosis (MS) leads to secondary axon degeneration and progressive disability. Therapies that potentiate remyelination would be of immense help for managing MS. Objective: Here, we report the effects of valproic acid (VPA) on focal experimental autoimmune encephalomyelitis (fEAE). Methods: fEAE was induced in Wistar rats by immunizing the animals with guinea pig spinal cord homog-enate emulsified in complete Freund's adjuvant and with pertussis toxin (PT) injection into the spinal cord at the level of T8 vertebra on day 18 after immunization. VPA 300 mg/kg was applied for 4 days after or 8 days before PT administration. Behavioral evaluation, histological assessment and im-munohistofluorescence assays were used to evaluate the outcomes. Results: VPA administration had no effect on the development of symptoms, but after discontinuing VPA, animals showed faster recovery. Eight days of pretreatment with VPA accelerated the recovery phase of EAE and increased the number of remyelinated axons in the lesion area. VPA pretreatment also increased the recruitment of neural stem cells and oligodendrocyte precursors within the lesion. Conclusions: Results suggest VPA as a potential therapy for remyelinating the lesions in MS and for faster recovery from disease relapses. The effect of VPA seems to be mediated by endogenous progenitors recruitment.