# Ursolic acid: a novel oral therapy for chronic stage of MS/EAE by both immunomodulation and neural repair

> **NIH NIH R01** · THOMAS JEFFERSON UNIVERSITY · 2021 · $341,250

## Abstract

Inflammatory demyelination and axonal damage of the central nervous system (CNS) are hallmarks
of the chronic stage of multiple sclerosis (MS) and its animal model, experimental autoimmune
encephalomyelitis (EAE). Current MS medications are mainly immunomodulatory, having little or no effect
on neuroregeneration of damaged CNS tissue; they are thus only effective in the acute, but not the
chronic stage of disease. An MS therapy that has both immunomodulatory and neuroregenerative effects
would be highly beneficial. This goal could be achieved by using ursolic acid (UA), a natural triterpenoid
compound found in plants that are widely present in the human diet and in anti-inflammatory medicinal
herbs. UA has been recently found to inhibit several types of inflammatory diseases and to prevent EAE
when i.p. injected before disease onset, by inhibiting Th1/Th17 cell differentiation. UA also protects
neurons from apoptosis. We, for the first time, show that oral UA effectively suppresses ongoing EAE
when treatment is started at both acute and chronic stages of EAE, and promotes remyelination in brain-
slice culture. Further, UA treatment significantly elevates expression of nuclear factor IL-3 (NFIL3), a
transcription factor that has both immunomodulatory and neuroreparative capacities, and lack of NFIL3
expression largely reduces UA effects.
 The central hypothesis of this proposal is that UA is a novel oral therapy for chronic MS/EAE thanks
to its dual effects of immunomodulation and direct neuroregeneration, through NFIL3-induced
mechanisms. Three specific aims are proposed to test this hypothesis. From the academic perspective,
we have dedicated Specific Aims 1 and 2 to investigation of the mechanisms of UA/NFIL3 action in
immunomodulation and neural repair, respectively. From the therapeutic perspective, we will in Specific
Aim 3 test the therapeutic effects of UA on the chronic stage of chronic-progressive (CP) and relapsing-
remitting (RR) EAE. In addition, potential side effects and safety issues of long-term oral UA will also be
closely monitored.
 This project, if successful, will provide evidence that UA has great potential as an oral anti-
inflammatory and neural repair agent for MS, especially at the chronic stage, for which there is currently
no effective therapy.

## Key facts

- **NIH application ID:** 10136729
- **Project number:** 5R01NS099594-05
- **Recipient organization:** THOMAS JEFFERSON UNIVERSITY
- **Principal Investigator:** GUANG-XIAN ZHANG
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $341,250
- **Award type:** 5
- **Project period:** 2017-06-01 → 2023-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10136729

## Citation

> US National Institutes of Health, RePORTER application 10136729, Ursolic acid: a novel oral therapy for chronic stage of MS/EAE by both immunomodulation and neural repair (5R01NS099594-05). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10136729. Licensed CC0.

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