Ursolic acid derivative UAOS-Na treats experimental autoimmune encephalomyelitis by immunoregulation and protecting myelin

Maolin Wang; Chenming Gu; Yifu Yang; Liang Chen; Kaixian Chen; Jun Du; Huali Wu; Yiming Li

doi:10.3389/fneur.2023.1269862

Ursolic acid derivative UAOS-Na treats experimental autoimmune encephalomyelitis by immunoregulation and protecting myelin

Front Neurol. 2023 Nov 30:14:1269862. doi: 10.3389/fneur.2023.1269862. eCollection 2023.

Authors

Maolin Wang^{1

2}, Chenming Gu¹, Yifu Yang³, Liang Chen⁴, Kaixian Chen¹, Jun Du⁴, Huali Wu¹, Yiming Li¹

Affiliations

¹ School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
² Department of Pharmacy, The Affiliated Hospital of Southwest Medical University, Luzhou, China.
³ Experiment Center for Science and Technology, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
⁴ Nutrition Science, Amway (Shanghai) Innovation and Science Co., Ltd., Shanghai, China.

Abstract

Introduction: Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS). Ursolic acid (UA) can be used in the MS treatment with anti-inflammatory and neuroprotective activities. However, UA is insoluble in water, which may affect its medication effectiveness. In our previous study, UAOS-Na, a water-soluble derivative of UA was obtained. In this study, we evaluated the pharmacological effects and explored its underlying mechanism of UAOS-Na on experimental autoimmune encephalomyelitis (EAE).

Methods: Firstly, the pharmacodynamics of UAOS-Na was investigated in EAE and Cuprizone-induced mice. And then the possible mechanisms were investigated by TMT proteomics and verified by in vitro and in vivo experiments.

Results: UAOS-Na (30 mg/kg/d) delayed the onset time of EAE from 11.78 days post immunization (dpi) to 14.33 dpi, reduced the incidence from 90.0% to 42.9%. UAOS-Na (60 mg/kg/d) reduced the serum levels of IFN-γ, IL-17A, TNF-α and IL-6, reduced the mononuclear cell infiltration of spinal cord, and inhibited the overexpression of key transcription factors T-bet and ROR-γt of EAE mouse spinal cord. In addition, UAOS-Na attenuated demyelination and astrogliosis in the CNS of EAE and cuprizone-induced mice. Mechanistically, proteomics showed that 96 differential expression proteins (DEPs) were enriched and 94 were upregulated in EAE mice compared with normal group. After UAOS-Na treatment, 16 DEPs were enriched and 15 were downregulated, and these DEPs were markedly enriched in antigen processing and presentation (APP) signaling pathway. Moreover, UAOS-Na downregulated the protein levels of Tapbp and H2-T23 in MHC-I antigen presentation pathway and reduced the proliferation of splenic CD8 T cells, thereby inhibiting the CNS infiltration of CD8 T cells.

Conclusion: Our findings demonstrated that UAOS-Na has both myelin protective and anti-inflammatory effects. And it could reduce the inflammation of MS by downregulating the expression of Tapbp and H2-T23 in the MHC-I antigen presentation pathway.

Keywords: H2-T23; MHC-I antigen presentation pathway; TAPBP; experimental autoimmune encephalomyelitis; ursolic acid.

Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This work was supported by the National Natural Science Foundation of China (81973458), the National Key Science and Technology Infrastructure (Shanghai) Translational Medicine Open Program (TMSK-2021-404), and Shanghai Scientific and Technological Innovation Program (18401931100).