Ligustilide improves functional constipation by non-covalently activating TRPA1 in colon tissue

Area of Science:

• Pharmacology
• Gastroenterology
• Natural Products Chemistry

Background:

• Angelica sinensis (AS) is a traditional herb for constipation, but its active compounds and mechanisms are not fully understood.
• Transient Receptor Potential (TRP) channels regulate gastrointestinal functions, including mucus secretion and motility, yet their link to AS's key compound, ligustilide (Lig), is unclear.

Purpose of the Study:

• To investigate the pharmacodynamics of AS in functional constipation.
• To evaluate ligustilide's (Lig) potential to activate TRP channels.
• To elucidate the molecular mechanism of Lig in alleviating constipation.

Main Methods:

• Assessed AS efficacy in a loperamide-induced constipation mouse model.
• Screened active pharmaceutical ingredients (APIs) using UPLC profiling and PAS staining.
• Identified Lig's target via target fishing and used molecular docking, MST, and FQ assays to determine interaction modes.

Main Results:

• AS improved functional constipation in mice, with ligustilide (Lig) identified as the key mucus-inducing component.
• Lig specifically targets and activates the TRPA1 channel in the colon, leading to calcium influx and increased mucus secretion.
• Lig binds to Thr684 in the TRPA1 pre-S1 region, triggering channel activation and ameliorating constipation.

Conclusions:

• Lig, an active pharmaceutical ingredient (API) in AS, treats constipation by activating TRPA1 via non-covalent interactions.
• This activation increases colonic mucus secretion, thereby improving functional constipation.
• Findings provide insight into AS and Lig's therapeutic mechanisms for constipation and suggest potential for TRPA1 agonist development.