Cargando…

MNK inhibitor eFT508 (Tomivosertib) suppresses ectopic activity in human dorsal root ganglion neurons from dermatomes with radicular neuropathic pain

Spontaneous activity in dorsal root ganglion (DRG) neurons is a key driver of neuropathic pain in preclinical models and in patients suffering from this largely untreated disease. While many intracellular signaling mechanisms have been examined in preclinical models that drive this spontaneous activ...

Descripción completa

Detalles Bibliográficos
Autores principales: Li, Yan, Uhelski, Megan L., North, Robert Y., Mwirigi, Juliet M., Tatsui, Claudio E., Cata, Juan P., Corrales, German, Price, Theodore J., Dougherty, Patrick M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cold Spring Harbor Laboratory 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10312735/
https://www.ncbi.nlm.nih.gov/pubmed/37398249
http://dx.doi.org/10.1101/2023.06.13.544811
_version_ 1785066977844264960
author Li, Yan
Uhelski, Megan L.
North, Robert Y.
Mwirigi, Juliet M.
Tatsui, Claudio E.
Cata, Juan P.
Corrales, German
Price, Theodore J.
Dougherty, Patrick M.
author_facet Li, Yan
Uhelski, Megan L.
North, Robert Y.
Mwirigi, Juliet M.
Tatsui, Claudio E.
Cata, Juan P.
Corrales, German
Price, Theodore J.
Dougherty, Patrick M.
author_sort Li, Yan
collection PubMed
description Spontaneous activity in dorsal root ganglion (DRG) neurons is a key driver of neuropathic pain in preclinical models and in patients suffering from this largely untreated disease. While many intracellular signaling mechanisms have been examined in preclinical models that drive this spontaneous activity (SA), none of these have been tested directly on spontaneously active human nociceptors. Using cultured DRG neurons recovered during thoracic vertebrectomy surgeries, we show that inhibition of mitogen activated protein kinase interacting kinase (MNK) with eFT508 (25 nM) reverses SA in human sensory neurons associated with painful dermatomes. MNK inhibition in spontaneously active nociceptors decreased action potential amplitude and produced alterations in the magnitude of afterhyperpolarizing currents suggesting modification of Na(+) and K(+) channel activity downstream of MNK inhibition. The effects of MNK inhibition on SA took minutes to emerge and were reversible over time with eFT508 washout. MNK inhibition with eFT508 led to a profound loss of eIF4E Serine 209 phosphorylation, a specific target of the kinase, within 2 min of drug treatment, consistent with the rapid action of the drug on SA in electrophysiology experiments. Our results create a compelling case for the future testing of MNK inhibitors in clinical trials for neuropathic pain.
format Online
Article
Text
id pubmed-10312735
institution National Center for Biotechnology Information
language English
publishDate 2023
publisher Cold Spring Harbor Laboratory
record_format MEDLINE/PubMed
spelling pubmed-103127352023-07-01 MNK inhibitor eFT508 (Tomivosertib) suppresses ectopic activity in human dorsal root ganglion neurons from dermatomes with radicular neuropathic pain Li, Yan Uhelski, Megan L. North, Robert Y. Mwirigi, Juliet M. Tatsui, Claudio E. Cata, Juan P. Corrales, German Price, Theodore J. Dougherty, Patrick M. bioRxiv Article Spontaneous activity in dorsal root ganglion (DRG) neurons is a key driver of neuropathic pain in preclinical models and in patients suffering from this largely untreated disease. While many intracellular signaling mechanisms have been examined in preclinical models that drive this spontaneous activity (SA), none of these have been tested directly on spontaneously active human nociceptors. Using cultured DRG neurons recovered during thoracic vertebrectomy surgeries, we show that inhibition of mitogen activated protein kinase interacting kinase (MNK) with eFT508 (25 nM) reverses SA in human sensory neurons associated with painful dermatomes. MNK inhibition in spontaneously active nociceptors decreased action potential amplitude and produced alterations in the magnitude of afterhyperpolarizing currents suggesting modification of Na(+) and K(+) channel activity downstream of MNK inhibition. The effects of MNK inhibition on SA took minutes to emerge and were reversible over time with eFT508 washout. MNK inhibition with eFT508 led to a profound loss of eIF4E Serine 209 phosphorylation, a specific target of the kinase, within 2 min of drug treatment, consistent with the rapid action of the drug on SA in electrophysiology experiments. Our results create a compelling case for the future testing of MNK inhibitors in clinical trials for neuropathic pain. Cold Spring Harbor Laboratory 2023-06-14 /pmc/articles/PMC10312735/ /pubmed/37398249 http://dx.doi.org/10.1101/2023.06.13.544811 Text en https://creativecommons.org/licenses/by/4.0/This work is licensed under a Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/) , which allows reusers to distribute, remix, adapt, and build upon the material in any medium or format, so long as attribution is given to the creator. The license allows for commercial use.
spellingShingle Article
Li, Yan
Uhelski, Megan L.
North, Robert Y.
Mwirigi, Juliet M.
Tatsui, Claudio E.
Cata, Juan P.
Corrales, German
Price, Theodore J.
Dougherty, Patrick M.
MNK inhibitor eFT508 (Tomivosertib) suppresses ectopic activity in human dorsal root ganglion neurons from dermatomes with radicular neuropathic pain
title MNK inhibitor eFT508 (Tomivosertib) suppresses ectopic activity in human dorsal root ganglion neurons from dermatomes with radicular neuropathic pain
title_full MNK inhibitor eFT508 (Tomivosertib) suppresses ectopic activity in human dorsal root ganglion neurons from dermatomes with radicular neuropathic pain
title_fullStr MNK inhibitor eFT508 (Tomivosertib) suppresses ectopic activity in human dorsal root ganglion neurons from dermatomes with radicular neuropathic pain
title_full_unstemmed MNK inhibitor eFT508 (Tomivosertib) suppresses ectopic activity in human dorsal root ganglion neurons from dermatomes with radicular neuropathic pain
title_short MNK inhibitor eFT508 (Tomivosertib) suppresses ectopic activity in human dorsal root ganglion neurons from dermatomes with radicular neuropathic pain
title_sort mnk inhibitor eft508 (tomivosertib) suppresses ectopic activity in human dorsal root ganglion neurons from dermatomes with radicular neuropathic pain
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10312735/
https://www.ncbi.nlm.nih.gov/pubmed/37398249
http://dx.doi.org/10.1101/2023.06.13.544811
work_keys_str_mv AT liyan mnkinhibitoreft508tomivosertibsuppressesectopicactivityinhumandorsalrootganglionneuronsfromdermatomeswithradicularneuropathicpain
AT uhelskimeganl mnkinhibitoreft508tomivosertibsuppressesectopicactivityinhumandorsalrootganglionneuronsfromdermatomeswithradicularneuropathicpain
AT northroberty mnkinhibitoreft508tomivosertibsuppressesectopicactivityinhumandorsalrootganglionneuronsfromdermatomeswithradicularneuropathicpain
AT mwirigijulietm mnkinhibitoreft508tomivosertibsuppressesectopicactivityinhumandorsalrootganglionneuronsfromdermatomeswithradicularneuropathicpain
AT tatsuiclaudioe mnkinhibitoreft508tomivosertibsuppressesectopicactivityinhumandorsalrootganglionneuronsfromdermatomeswithradicularneuropathicpain
AT catajuanp mnkinhibitoreft508tomivosertibsuppressesectopicactivityinhumandorsalrootganglionneuronsfromdermatomeswithradicularneuropathicpain
AT corralesgerman mnkinhibitoreft508tomivosertibsuppressesectopicactivityinhumandorsalrootganglionneuronsfromdermatomeswithradicularneuropathicpain
AT pricetheodorej mnkinhibitoreft508tomivosertibsuppressesectopicactivityinhumandorsalrootganglionneuronsfromdermatomeswithradicularneuropathicpain
AT doughertypatrickm mnkinhibitoreft508tomivosertibsuppressesectopicactivityinhumandorsalrootganglionneuronsfromdermatomeswithradicularneuropathicpain