Mannose-dependent TrkA modulation by Gastrodia elata lectins attenuates peripheral nociception: Potential as natural...

Native plant proteins are increasingly recognized as functional components whose biological activities are governed by their specific molecular structures. In this study, we isolated and purified two low-molecular-weight mannose-binding lectins from the edible plant G. elata, designated FGEP-1 (13 kDa) and FGEP-2 (12 kDa). Proteomic analysis and N-terminal sequencing identified FGEP-1 as chain A gastrodianin-4, while FGEP-2 was characterized as a putative novel variant with distinct amino acid substitutions. In vitro screening confirmed their safety, showing no hemolysis or cytotoxicity across multiple mammalian cell lines Mechanistically, surface plasmon resonance (SPR) and molecular docking confirmed that both lectins bind TrkA receptor through mannose-dependent recognition (KD values of 4.90 and 7.06 μM), with N281 predicted as a potential key glycosylation site for the interaction. This binding suppressed NGF-induced TrkA phosphorylation and luciferase reporter activity in vitro. In vivo, administration of FGEP-1 or FGEP-2 dose-dependently attenuated NGF-induced thermal hyperalgesia in mice. Immunofluorescence analysis further revealed that these lectins suppressed p-TrkA levels in the dorsal root ganglia (DRG), consistent with the observed behavioral outcomes. Subsequent H&E staining confirmed that DRG tissue architecture remained preserved without overt lesions under the effective dosing regimen. Collectively, this study not only uncovers the biomolecular mechanism of lectin-TrkA interaction but also provides a crucial in vivo proof-of-concept for the analgesic potential of G. elata-derived proteins, paving the way for their future application as plant-based functional bioactives.