Current immunomodulatory therapies for multiple sclerosis (MS) can effectively inhibit autoimmune response, but largely fail to promote myelin repair. This therapeutic deficiency is due mainly to the failure of treatment to promote remyelination in the central nervous system (CNS). Here we show that ursolic acid (UA), a natural triterpenoid, in addition to its well-known antiinflammatory effect, also directly stimulates oligodendrocyte maturation and CNS myelin repair. Mechanisms of UA action involve induction of pro-myelinating neurotrophic factor in astrocytes by PPARγ/CREB signaling and regulation of myelin-related gene expression during oligodendrocyte maturation via PPARγ activation. Our data demonstrate that UA has great potential as an agent for MS, especially at the chronic-progressive stage, because of its capacity in both immunomodulation and neural repair.

Abstract

Current multiple sclerosis (MS) medications are mainly immunomodulatory, having little or no effect on neuroregeneration of damaged central nervous system (CNS) tissue; they are thus primarily effective at the acute stage of disease, but much less so at the chronic stage. An MS therapy that has both immunomodulatory and neuroregenerative effects would be highly beneficial. Using multiple in vivo and in vitro strategies, in the present study we demonstrate that ursolic acid (UA), an antiinflammatory natural triterpenoid, also directly promotes oligodendrocyte maturation and CNS myelin repair. Oral treatment with UA significantly decreased disease severity and CNS inflammation and demyelination in experimental autoimmune encephalomyelitis (EAE), an animal model of MS. Importantly, remyelination and neural repair in the CNS were observed even after UA treatment was started on day 60 post immunization when EAE mice had full-blown demyelination and axonal damage. UA treatment also enhanced remyelination in a cuprizone-induced demyelination model in vivo and brain organotypic slice cultures ex vivo and promoted oligodendrocyte maturation in vitro, indicating a direct myelinating capacity. Mechanistically, UA induced promyelinating neurotrophic factor CNTF in astrocytes by peroxisome proliferator-activated receptor γ(PPARγ)/CREB signaling, as well as by up-regulation of myelin-related gene expression during oligodendrocyte maturation via PPARγ activation. Together, our findings demonstrate that UA has significant potential as an oral antiinflammatory and neural repair agent for MS, especially at the chronic-progressive stage.