Glucotropaeolin-enriched Lepidium sativum L. extract as a novel phytotherapy for tendinopathy: mechanistic insights into pain modulation

Objective: Tendinopathy is a clinical condition marked by pain and impaired tendon function. Given the limited efficacy of conventional therapies, phytotherapeutic and nutraceutical strategies have gained attention. Brassicaceae plants, particularly Lepidium sativum L., contain bioactive compounds such as glucosinolates, notably glucotropaeolin, with potential benefits in chronic pain. The aim of the study was to evaluate the therapeutic potential of a L. sativum seed extract in tendinopathy. Methods: Tendon damage was induced in mice via intra-tendinous collagenase injection. Both systemic (oral) and local (peritendinous) administrations of L. sativum extract were tested for anti-hyperalgesic effects and compared with isolated glucotropaeolin. Pharmacological and histological mechanistic analyses were conducted. Results: Oral administration of the L. sativum extract (13-130 mg kg-1, equivalent to 10-100 µmol kg-1 glucotropaeolin) dose-dependently reduced tendinopathy-related pain. Pharmacodynamic investigations showed that glucotropaeolin undergoes hydrolysis in vivo, releasing hydrogen sulfide (H₂S), which activates Kv7 potassium channels involved in pain modulation. Local administration of glucotropaeolin (10-100 µmol mL-1; 50 µL) significantly reduced tendon pain, while the extract showed reduced efficacy peritendinously. Repeated administration of the L. sativum extract (40 mg kg-1 orally) or glucotropaeolin (30 µmol mL-1 peritendinously) for ten days attenuated spontaneous pain, mechanical hyperalgesia, and exercise-induced exacerbation. Although these treatments did not prevent tendon degeneration, the extract markedly decreased mast cell infiltration and substance P levels in tendon tissue. Notably, unlike conventional anti-inflammatory drugs such as NSAIDs, which in preclinical collagenase-induced tendinopathy chiefly reduce early inflammation without improving tendon repair, L. sativum extract demonstrated a broader pharmacological profile with both anti-hyperalgesic and immunomodulatory efficacy. Conclusion: L. sativum exhibits significant potential in the symptomatic and therapeutic management of tendinopathy, mainly through glucotropaeolin-mediated modulation of pain pathways.