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.

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.