Identification of novel regulators of Zalcitabine-Induced neuropathic pain
Neuropathic pain is one of the foremost adverse effects that worsens quality of life for patients undergoing an antiretroviral treatment. Currently, there are no effective analgesics for relieving it; thus, there is an urgent need to develop novel treatments for neuropathic pain. Previously, we desc...
| Autores: | , , , , , , , , , , , |
|---|---|
| Tipo de recurso: | artículo |
| Fecha de publicación: | 2021 |
| País: | España |
| Institución: | Universidad de Santiago de Compostela (USC) |
| Repositorio: | Minerva. Repositorio Institucional de la Universidad de Santiago de Compostela |
| Idioma: | inglés |
| OAI Identifier: | oai:minerva.usc.gal:10347/45062 |
| Acceso en línea: | https://hdl.handle.net/10347/45062 |
| Access Level: | acceso abierto |
| Palabra clave: | Neuropathic pain Antiretrovirals Hyperexcitability, Alcium transients Transcriptomic assays Adverse effects |
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Identification of novel regulators of Zalcitabine-Induced neuropathic painMartínez Rodríguez, Antón LeandroBrea Floriani, José ManuelDomínguez Medina, EduardoVarela Liste, María JoséCimadevila Fondevila, MartaAllegue Toscano, CatarinaCruz Guerrero, RaquelMonroy, XavierMerlos, ManuelBurgueño, JavierCarracedo Álvarez, ÁngelLoza García, María IsabelNeuropathic painAntiretroviralsHyperexcitability,Alcium transientsTranscriptomic assaysAdverse effectsNeuropathic pain is one of the foremost adverse effects that worsens quality of life for patients undergoing an antiretroviral treatment. Currently, there are no effective analgesics for relieving it; thus, there is an urgent need to develop novel treatments for neuropathic pain. Previously, we described and validated F11 cells as a model of DRG (dorsal root ganglia) neurons. In the current work, we employed F11 cells to identify regulators of antiretroviral-induced neuropathic pain combining functional and transcriptomic analysis. The antiretroviral zalcitabine (ddC) increased the excitability of differentiated F11 cells associated with calcium signaling without morphological changes in the neuronal phenotype, mimicking the observed increase of painful signaling in patients suffering from antiretroviral-induced neuropathic pain. Employing RNA sequencing, we observed that zalcitabine treatment upregulated genes related with oxidative stress and calcium homeostasis. The functional impact of the transcriptomic changes was explored, finding that the exposure to zalcitabine significantly increased intracellular oxidative stress and reduced store-operated calcium entry (SOCE). Because the functional and transcriptomic evidence points toward fundamental changes in calcium signaling and oxidative stress upon zalcitabine exposure, we identified that NAD(P)H quinone dehydrogenase and the sarcoplasmic/endoplasmic reticulum calcium ATPase 3 were involved in zalcitabine-induced hyperexcitability of F11 cells. Overexpression of those genes increases the calcium-elicited hyperexcitability response and reduces SOCE, as well as increases intracellular ROS levels. These data do not only mimic the effects of zalcitabine but also highlight the relevance of oxidative stress and of calcium-mediated signaling in antiretroviral-induced hyperexcitability of sensory neurons, shedding light on new therapeutic targets for antiviral-induced neuropathic painACS PublicationsUniversidade de Santiago de Compostela. Centro de Investigación en Medicina Molecular e Enfermidades Crónicas (CiMUS)Universidade de Santiago de Compostela. Departamento de Farmacoloxía, Farmacia e Tecnoloxía Farmacéutica20212021-06-2920212021-06-29journal articlehttp://purl.org/coar/resource_type/c_6501VoRhttp://purl.org/coar/version/c_970fb48d4fbd8a85info:eu-repo/semantics/articleapplication/pdfhttps://hdl.handle.net/10347/45062reponame:Minerva. Repositorio Institucional de la Universidad de Santiago de Compostelainstname:Universidad de Santiago de Compostela (USC)InglésengAgencia Estatal de Investigación http://dx.doi.org/10.13039/501100011033 Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020 RTC-2015-4207-1 Desarrollo de Modelos Fenotípicos In Vitro de Dolor y su Aplicación al Cribado de Compuestos de Alto Rendimiento (High-Throughput Screening)open accesshttp://purl.org/coar/access_right/c_abf2© 2021 The Authors. Published by American Chemical Society. This publication is licensed under CC-BY-NC-ND 4.0http://creativecommons.org/licenses/by-nc-nd/4.0/info:eu-repo/semantics/openAccessoai:minerva.usc.gal:10347/450622026-06-15T12:47:27Z |
| dc.title.none.fl_str_mv |
Identification of novel regulators of Zalcitabine-Induced neuropathic pain |
| title |
Identification of novel regulators of Zalcitabine-Induced neuropathic pain |
| spellingShingle |
Identification of novel regulators of Zalcitabine-Induced neuropathic pain Martínez Rodríguez, Antón Leandro Neuropathic pain Antiretrovirals Hyperexcitability, Alcium transients Transcriptomic assays Adverse effects |
| title_short |
Identification of novel regulators of Zalcitabine-Induced neuropathic pain |
| title_full |
Identification of novel regulators of Zalcitabine-Induced neuropathic pain |
| title_fullStr |
Identification of novel regulators of Zalcitabine-Induced neuropathic pain |
| title_full_unstemmed |
Identification of novel regulators of Zalcitabine-Induced neuropathic pain |
| title_sort |
Identification of novel regulators of Zalcitabine-Induced neuropathic pain |
| dc.creator.none.fl_str_mv |
Martínez Rodríguez, Antón Leandro Brea Floriani, José Manuel Domínguez Medina, Eduardo Varela Liste, María José Cimadevila Fondevila, Marta Allegue Toscano, Catarina Cruz Guerrero, Raquel Monroy, Xavier Merlos, Manuel Burgueño, Javier Carracedo Álvarez, Ángel Loza García, María Isabel |
| author |
Martínez Rodríguez, Antón Leandro |
| author_facet |
Martínez Rodríguez, Antón Leandro Brea Floriani, José Manuel Domínguez Medina, Eduardo Varela Liste, María José Cimadevila Fondevila, Marta Allegue Toscano, Catarina Cruz Guerrero, Raquel Monroy, Xavier Merlos, Manuel Burgueño, Javier Carracedo Álvarez, Ángel Loza García, María Isabel |
| author_role |
author |
| author2 |
Brea Floriani, José Manuel Domínguez Medina, Eduardo Varela Liste, María José Cimadevila Fondevila, Marta Allegue Toscano, Catarina Cruz Guerrero, Raquel Monroy, Xavier Merlos, Manuel Burgueño, Javier Carracedo Álvarez, Ángel Loza García, María Isabel |
| author2_role |
author author author author author author author author author author author |
| dc.contributor.none.fl_str_mv |
Universidade de Santiago de Compostela. Centro de Investigación en Medicina Molecular e Enfermidades Crónicas (CiMUS) Universidade de Santiago de Compostela. Departamento de Farmacoloxía, Farmacia e Tecnoloxía Farmacéutica |
| dc.subject.none.fl_str_mv |
Neuropathic pain Antiretrovirals Hyperexcitability, Alcium transients Transcriptomic assays Adverse effects |
| topic |
Neuropathic pain Antiretrovirals Hyperexcitability, Alcium transients Transcriptomic assays Adverse effects |
| description |
Neuropathic pain is one of the foremost adverse effects that worsens quality of life for patients undergoing an antiretroviral treatment. Currently, there are no effective analgesics for relieving it; thus, there is an urgent need to develop novel treatments for neuropathic pain. Previously, we described and validated F11 cells as a model of DRG (dorsal root ganglia) neurons. In the current work, we employed F11 cells to identify regulators of antiretroviral-induced neuropathic pain combining functional and transcriptomic analysis. The antiretroviral zalcitabine (ddC) increased the excitability of differentiated F11 cells associated with calcium signaling without morphological changes in the neuronal phenotype, mimicking the observed increase of painful signaling in patients suffering from antiretroviral-induced neuropathic pain. Employing RNA sequencing, we observed that zalcitabine treatment upregulated genes related with oxidative stress and calcium homeostasis. The functional impact of the transcriptomic changes was explored, finding that the exposure to zalcitabine significantly increased intracellular oxidative stress and reduced store-operated calcium entry (SOCE). Because the functional and transcriptomic evidence points toward fundamental changes in calcium signaling and oxidative stress upon zalcitabine exposure, we identified that NAD(P)H quinone dehydrogenase and the sarcoplasmic/endoplasmic reticulum calcium ATPase 3 were involved in zalcitabine-induced hyperexcitability of F11 cells. Overexpression of those genes increases the calcium-elicited hyperexcitability response and reduces SOCE, as well as increases intracellular ROS levels. These data do not only mimic the effects of zalcitabine but also highlight the relevance of oxidative stress and of calcium-mediated signaling in antiretroviral-induced hyperexcitability of sensory neurons, shedding light on new therapeutic targets for antiviral-induced neuropathic pain |
| publishDate |
2021 |
| dc.date.none.fl_str_mv |
2021 2021-06-29 2021 2021-06-29 |
| dc.type.none.fl_str_mv |
journal article http://purl.org/coar/resource_type/c_6501 VoR http://purl.org/coar/version/c_970fb48d4fbd8a85 |
| dc.type.openaire.fl_str_mv |
info:eu-repo/semantics/article |
| format |
article |
| dc.identifier.none.fl_str_mv |
https://hdl.handle.net/10347/45062 |
| url |
https://hdl.handle.net/10347/45062 |
| dc.language.none.fl_str_mv |
Inglés eng |
| language_invalid_str_mv |
Inglés |
| language |
eng |
| dc.relation.none.fl_str_mv |
Agencia Estatal de Investigación http://dx.doi.org/10.13039/501100011033 Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020 RTC-2015-4207-1 Desarrollo de Modelos Fenotípicos In Vitro de Dolor y su Aplicación al Cribado de Compuestos de Alto Rendimiento (High-Throughput Screening) |
| dc.rights.none.fl_str_mv |
open access http://purl.org/coar/access_right/c_abf2 http://creativecommons.org/licenses/by-nc-nd/4.0/ |
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info:eu-repo/semantics/openAccess |
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open access http://purl.org/coar/access_right/c_abf2 http://creativecommons.org/licenses/by-nc-nd/4.0/ |
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openAccess |
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application/pdf |
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ACS Publications |
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ACS Publications |
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reponame:Minerva. Repositorio Institucional de la Universidad de Santiago de Compostela instname:Universidad de Santiago de Compostela (USC) |
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