Next Article in Journal
Proteomics of Bacterial and Mouse Extracellular Vesicles Released in the Gastrointestinal Tracts of Nutrient-Stressed Animals Reveals an Interplay Between Microbial Serine Proteases and Mammalian Serine Protease Inhibitors
Previous Article in Journal
Rekindling Vision: Innovative Strategies for Treating Retinal Degeneration
Previous Article in Special Issue
Bulge-Derived Epithelial Cells Isolated from Human Hair Follicles Using Enzymatic Digestion or Explants Result in Comparable Tissue-Engineered Skin
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
IJMS
Volume 26
Issue 9
10.3390/ijms26094079
ijms-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Article

Interaction of Erdosteine with TrkA Signaling Pathways: Implications for Analgesia

by
Nicoletta Marchesi
1,
Stefano Govoni
1,
Clive P. Page
2,
Luda Diatchenko
3,
Alessia Pascale
1,*,
Piercarlo Fantucci
4,
Jacopo Vertemara
4,
Silvia Natoli
5,6 and
Massimo Allegri
7
1
Department of Drug Sciences, Pharmacology Section, University of Pavia, 27100 Pavia, Italy
2
Institute of Pharmaceutical Science, King’s College London, London SE1 9NH, UK
3
Faculty of Dental Medicine and Oral Health Sciences, Department of Anesthesia, Faculty of Medicine, Alan Edwards Centre for Research on Pain, McGill University, Montreal, QC H3A 1G1, Canada
4
Department of Biotechnology and Biosciences, University of Milan-Bicocca, 20126 Milan, Italy
5
Department of Clinical-Surgical, Diagnostic and Pediatric Sciences, University of Pavia, 27100 Pavia, Italy
6
IRCCS Policlinco San Matteo, 27100 Pavia, Italy
7
Centre Lémanique de Neuromodulation et Thérapie de la Douleur, Ensemble Hospitalier de la Côte (EHC), 1110 Morges, Switzerland
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2025, 26(9), 4079; https://doi.org/10.3390/ijms26094079
Submission received: 20 March 2025 / Revised: 19 April 2025 / Accepted: 23 April 2025 / Published: 25 April 2025
(This article belongs to the Collection Feature Paper Collection in Biochemistry)
Browse Figures
Versions Notes

Abstract

Thiol-containing drugs may interact with a region of tropomyosin receptor kinase A (TrkA), potentially inhibiting its activation by nerve growth factor (NGF). This action has been linked to potential analgesic activities. Here, we describe the ability of erdosteine, a thiolic compound classified as a mucolytic agent, to bind to the TrkA receptor sequence in silico and its in vitro effects on TrkA activation induced by NGF in cultured human neuroblastoma cells. Our results show that erdosteine and its metabolite, Met-1, bind to the TrkA receptor pocket, involving the primary TrkA residues Glu331, Arg347, His298, and His297. Furthermore, Met-1 has the ability to reduce the disulfide bridge between Cys300 and Cys345 of TrkA. In vitro measurement of TrkA autophosphorylation following NGF activation confirmed that erdosteine and Met-1 interfere with NGF-induced TrkA activation, leading to a consequent loss of the molecular recognition and spatial reorganization necessary for the induction of the autophosphorylation process. This effect was inhibited by low millimolar concentrations of the two compounds, reaching a maximal inhibition (around 40%) after 24 h of exposure to 1 mM erdosteine, and then plateauing. These findings suggest that erdosteine can act as a TrkA antagonist, thus indicating that this drug may have potential as an analgesic via a novel non-opioid mechanism of action operating through NGF signaling inhibition at the level of TrkA.
Keywords: pain; non-opioid drugs; NGF; TrkA; drug repurposing pain; non-opioid drugs; NGF; TrkA; drug repurposing

Share and Cite

MDPI and ACS Style

Marchesi, N.; Govoni, S.; Page, C.P.; Diatchenko, L.; Pascale, A.; Fantucci, P.; Vertemara, J.; Natoli, S.; Allegri, M. Interaction of Erdosteine with TrkA Signaling Pathways: Implications for Analgesia. Int. J. Mol. Sci. 2025, 26, 4079. https://doi.org/10.3390/ijms26094079

AMA Style

Marchesi N, Govoni S, Page CP, Diatchenko L, Pascale A, Fantucci P, Vertemara J, Natoli S, Allegri M. Interaction of Erdosteine with TrkA Signaling Pathways: Implications for Analgesia. International Journal of Molecular Sciences. 2025; 26(9):4079. https://doi.org/10.3390/ijms26094079

Chicago/Turabian Style

Marchesi, Nicoletta, Stefano Govoni, Clive P. Page, Luda Diatchenko, Alessia Pascale, Piercarlo Fantucci, Jacopo Vertemara, Silvia Natoli, and Massimo Allegri. 2025. "Interaction of Erdosteine with TrkA Signaling Pathways: Implications for Analgesia" International Journal of Molecular Sciences 26, no. 9: 4079. https://doi.org/10.3390/ijms26094079

APA Style

Marchesi, N., Govoni, S., Page, C. P., Diatchenko, L., Pascale, A., Fantucci, P., Vertemara, J., Natoli, S., & Allegri, M. (2025). Interaction of Erdosteine with TrkA Signaling Pathways: Implications for Analgesia. International Journal of Molecular Sciences, 26(9), 4079. https://doi.org/10.3390/ijms26094079

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop