A dual effect of ursolic acid to the treatment of multiple sclerosis through both immunomodulation and direct remyelination
- 6 April 2020
- journal article
- research article
- Published by Proceedings of the National Academy of Sciences in Proceedings of the National Academy of Sciences of the United States of America
- Vol. 117 (16), 9082-9093
- https://doi.org/10.1073/pnas.2000208117
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.Keywords
Funding Information
- DH | National Institute for Health Research (NS099594; AI135601)
- Chinese National Natural Science Foundation (81771345; 31970771)
This publication has 45 references indexed in Scilit:
- Ursolic acid facilitates apoptosis in rheumatoid arthritis synovial fibroblasts by inducing SP1‐mediated Noxa expression and proteasomal degradation of Mcl‐1The FASEB Journal, 2018
- Ursolic acid derivatives for pharmaceutical use: a patent review (2012-2016)Expert Opinion on Therapeutic Patents, 2017
- Drug-based modulation of endogenous stem cells promotes functional remyelination in vivoNature, 2015
- Low and high doses of ursolic acid ameliorate experimental autoimmune myasthenia gravis through different pathwaysJournal of Neuroimmunology, 2015
- Ursolic acid, a potential PPARγ agonist, suppresses ovalbumin-induced airway inflammation and Penh by down-regulating IL-5, IL-13, and IL-17 in a mouse model of allergic asthmaEuropean Journal of Pharmacology, 2013
- S-Nitrosoglutathione Induces Ciliary Neurotrophic Factor Expression in Astrocytes, Which Has Implications to Protect the Central Nervous System under Pathological ConditionsPublished by Elsevier BV ,2013
- A phase I pharmacokinetic study of ursolic acid nanoliposomes in healthy volunteers and patients with advanced solid tumorsInternational Journal of Nanomedicine, 2013
- Peroxisome Proliferator-Activated Receptor-γ Agonists Promote Differentiation and Antioxidant Defenses of Oligodendrocyte Progenitor CellsJournal of Neuropathology and Experimental Neurology, 2009
- Association of a null mutation in the CNTF gene with early onset of multiple sclerosis.Archives of Neurology, 2002
- Regional distribution, developmental changes, and cellular localization of CNTF-mRNA and protein in the rat brain.The Journal of cell biology, 1991