2. Academic Validation
  3. Astragaloside II, a natural saponin, facilitates remyelination in demyelination neurological diseases via p75NTR receptor mediated β-catenin/Id2/MBP signaling axis in oligodendrocyte precursor cells

Astragaloside II, a natural saponin, facilitates remyelination in demyelination neurological diseases via p75NTR receptor mediated β-catenin/Id2/MBP signaling axis in oligodendrocyte precursor cells

  • J Adv Res. 2025 Apr 19:S2090-1232(25)00273-5. doi: 10.1016/j.jare.2025.04.028.
Jinfeng Yuan 1,  Yanlin Tao 2,  Mengxue Wang 3,  Yufeng Chen 3,  Xinyan Han 3,  Hui Wu 4,  Hailin Shi 3,  Fei Huang 3,  Xiaojun Wu 5
Affiliations

Affiliations

  • 1 Shanghai Key Laboratory of Compound Chinese Medicines, The Ministry of Education (MOE) Key Laboratory for Standardization of Chinese Medicines, The MOE Innovation Center for Basic Medicine Research on Qi-Blood TCM Theories, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China; Institute of Cardiovascular Disease of Integrated Traditional Chinese and Western Medicine, Shuguang Hospital affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
  • 2 Shanghai Key Laboratory of Compound Chinese Medicines, The Ministry of Education (MOE) Key Laboratory for Standardization of Chinese Medicines, The MOE Innovation Center for Basic Medicine Research on Qi-Blood TCM Theories, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China; Institute for Translational Brain Research, Fudan University, Shanghai 200433, China.
  • 3 Shanghai Key Laboratory of Compound Chinese Medicines, The Ministry of Education (MOE) Key Laboratory for Standardization of Chinese Medicines, The MOE Innovation Center for Basic Medicine Research on Qi-Blood TCM Theories, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
  • 4 Shanghai Key Laboratory of Compound Chinese Medicines, The Ministry of Education (MOE) Key Laboratory for Standardization of Chinese Medicines, The MOE Innovation Center for Basic Medicine Research on Qi-Blood TCM Theories, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China. Electronic address: zgykdxwuhui@foxmail.com.
  • 5 Shanghai Key Laboratory of Compound Chinese Medicines, The Ministry of Education (MOE) Key Laboratory for Standardization of Chinese Medicines, The MOE Innovation Center for Basic Medicine Research on Qi-Blood TCM Theories, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China. Electronic address: xiaojunwu320@126.com.
PMID: 40258474 DOI: 10.1016/j.jare.2025.04.028
Abstract

Background: Demyelination is a hallmark of neurological disorders such as multiple sclerosis and neuromyelitis optica, leading to neurological deficits. Existing therapies primarily modulate immune responses but lack efficacy in directly promoting myelin repair. Enhancing oligodendrocyte precursor cell (OPC) differentiation and oligodendrocytes (OLs) production is crucial for restoring myelin integrity.

Objectives: This study investigated the therapeutic potential of astragaloside II (AS-II), a bioactive saponin with neuroprotective and pro-differentiation properties, derived from Astragalus membranaceus, uniquely in promoting OPC differentiation and myelin endogenous repair, distinguishing it from existing immunomodulatory treatments. AS-II directly targets p75 neurotrophin receptor (p75NTR) signaling, a pathway linked to myelin regeneration but underestimated in current remyelination strategies.

Methods: We conducted in vitro OPC differentiation assays and in vivo demyelination models, including cuprizone and experimental autoimmune encephalomyelitis. Drug affinity responsive target stability mass spectrometry, cellular thermal shift assay, and surface plasmon resonance assays identified and validated p75NTR as the direct target of AS-II. p75NTR knockout mice and lentiviral transduction were used to confirm its role.

Results: AS-II improved neurobehavioral outcomes, increased OLs production, and enhanced myelin integrity by suppressing β-catenin/Id2/MBP signaling. Mechanistically, AS-II bound to p75NTR (Pro253, Ser257), stabilizing its structure and promoting remyelination. In p75NTR knockout mice, AS-II failed to restore myelin or neural function, confirming its p75NTR-dependent mechanism.

Conclusion: AS-II represents a novel therapeutic candidate for demyelinating diseases, offering a targeted approach to myelin regeneration through direct p75NTR modulation and addressing gaps in current treatment strategies.

Keywords

Astragaloside II; Demyelinating diseases; Myelin regeneration; Oligodendrocyte progenitor cells; p75NTR signaling; β-catenin/Id2/MBP axis.

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