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

Abstract

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 homogenate 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 immunohistofluorescence 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.

The use of valproic acid and multiple sclerosis

“…Previous animal studies have suggested that HDAC inhibitors might have a beneficial effect on the progression of EAE . A single study found that despite a beneficial effect on the remyelination and severity of symptoms, VPA appeared to have no effect on the development of EAE symptoms . We found no association between current VPA use and risk of MS, which is compatible with the observation of no protective effect of VPA in the aforementioned animal model of MS.…”

“…Previous animal studies have suggested that HDAC inhibitors might have a beneficial effect on the progression of EAE . A single study found that despite a beneficial effect on the remyelination and severity of symptoms, VPA appeared to have no effect on the development of EAE symptoms .…”

“…demonstrated that trichostatin (yet another HDAC inhibitor) reduced spinal cord inflammation, neuronal loss, and ameliorated disability in the relapsing phase of EAE, and Pazhoohan et al . showed that VPA reduced clinical disease severity of EAE, especially in the recovery phase, and accelerated remyelination …”

“…Although some controversy does exist, HDAC inhibitors are at the moment suggested to be of therapeutic relevance to MS . VPA is the only widely used human drug with an HDAC inhibitory effect .…”

Stem Cell Therapy: A Promising Therapeutic Approach for Multiple Sclerosis

“…In addition, other factors such as bFGF, EGF, and BDNF have also been shown to enhance neurogenesis and eventually enhance functional recovery in animal models of neurological disease (198)(199)(200). Administration of valproic acid has been shown to attenuate symptoms of EAE, and increase endogenous myelin repair by recruiting NSCs and oligodendrocyte progenitors to the lesion sites (201). Moreover, treatment of EAE animals with polymerized nanocurcumin showed promising results in enhancing neuroprotection and myelin repair (202).…”