Forsythoside A alleviates experimental autoimmune encephalomyelitis by targeting Tnfaip2

Area of Science:

• Neuroimmunology
• Pharmacology
• Molecular Biology

Background:

• Multiple sclerosis (MS) is a severe neuroinflammatory condition.
• Experimental autoimmune encephalomyelitis (EAE) serves as a key animal model for MS research.
• Forsythoside A (FA), a natural compound, shows potential anti-inflammatory and neuroprotective effects, but its role in EAE requires elucidation.

Purpose of the Study:

• To investigate the therapeutic efficacy of Forsythoside A (FA) in the EAE model.
• To elucidate the underlying molecular mechanisms of FA's action in EAE.

Main Methods:

• EAE was induced in mice, followed by treatment with varying doses of FA.
• Evaluated clinical outcomes, histopathology, immune cell profiles (flow cytometry), and gene expression (RNA sequencing).
• Utilized network pharmacology, molecular docking, molecular dynamics, and surface plasmon resonance to identify and validate FA's molecular target, Tnfaip2. In vitro studies confirmed the mechanism in BV2 microglia.

Main Results:

• FA treatment dose-dependently reduced clinical symptoms, CNS inflammation, and demyelination in EAE mice, particularly at 60 mg/kg.
• FA suppressed peripheral Th1 cell proliferation and microglial activation, decreasing pro-inflammatory markers.
• FA directly binds to TNF-α-induced protein 2 (Tnfaip2), inhibiting the Tnfaip2/NF-κB pathway and pro-inflammatory microglial polarization.

Conclusions:

• Forsythoside A ameliorates EAE by targeting Tnfaip2 and inhibiting the NF-κB pathway, thereby suppressing pro-inflammatory microglial responses.
• The Tnfaip2/NF-κB signaling axis represents a promising therapeutic target for managing multiple sclerosis.