Cargando…

Epothilone D alters normal growth, viability and microtubule dependent intracellular functions of cortical neurons in vitro

Brain penetrant microtubule stabilising agents (MSAs) are being increasingly validated as potential therapeutic strategies for neurodegenerative diseases and traumatic injuries of the nervous system. MSAs are historically used to treat malignancies to great effect. However, this treatment strategy c...

Descripción completa

Detalles Bibliográficos
Autores principales: Clark, J. A., Chuckowree, J. A., Dyer, M. S., Dickson, T. C., Blizzard, C. A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6976590/
https://www.ncbi.nlm.nih.gov/pubmed/31969604
http://dx.doi.org/10.1038/s41598-020-57718-z
_version_ 1783490335749439488
author Clark, J. A.
Chuckowree, J. A.
Dyer, M. S.
Dickson, T. C.
Blizzard, C. A.
author_facet Clark, J. A.
Chuckowree, J. A.
Dyer, M. S.
Dickson, T. C.
Blizzard, C. A.
author_sort Clark, J. A.
collection PubMed
description Brain penetrant microtubule stabilising agents (MSAs) are being increasingly validated as potential therapeutic strategies for neurodegenerative diseases and traumatic injuries of the nervous system. MSAs are historically used to treat malignancies to great effect. However, this treatment strategy can also cause adverse off-target impacts, such as the generation of debilitating neuropathy and axonal loss. Understanding of the effects that individual MSAs have on neurons of the central nervous system is still incomplete. Previous research has revealed that aberrant microtubule stabilisation can perturb many neuronal functions, such as neuronal polarity, neurite outgrowth, microtubule dependant transport and overall neuronal viability. In the current study, we evaluate the dose dependant impact of epothilone D, a brain penetrant MSA, on both immature and relatively mature mouse cortical neurons in vitro. We show that epothilone D reduces the viability, growth and complexity of immature cortical neurons in a dose dependant manner. Furthermore, in relatively mature cortical neurons, we demonstrate that while cellularly lethal doses of epothilone D cause cellular demise, low sub lethal doses can also affect mitochondrial transport over time. Our results reveal an underappreciated mitochondrial disruption over a wide range of epothilone D doses and reiterate the importance of understanding the dosage, timing and intended outcome of MSAs, with particular emphasis on brain penetrant MSAs being considered to target neurons in disease and trauma.
format Online
Article
Text
id pubmed-6976590
institution National Center for Biotechnology Information
language English
publishDate 2020
publisher Nature Publishing Group UK
record_format MEDLINE/PubMed
spelling pubmed-69765902020-01-29 Epothilone D alters normal growth, viability and microtubule dependent intracellular functions of cortical neurons in vitro Clark, J. A. Chuckowree, J. A. Dyer, M. S. Dickson, T. C. Blizzard, C. A. Sci Rep Article Brain penetrant microtubule stabilising agents (MSAs) are being increasingly validated as potential therapeutic strategies for neurodegenerative diseases and traumatic injuries of the nervous system. MSAs are historically used to treat malignancies to great effect. However, this treatment strategy can also cause adverse off-target impacts, such as the generation of debilitating neuropathy and axonal loss. Understanding of the effects that individual MSAs have on neurons of the central nervous system is still incomplete. Previous research has revealed that aberrant microtubule stabilisation can perturb many neuronal functions, such as neuronal polarity, neurite outgrowth, microtubule dependant transport and overall neuronal viability. In the current study, we evaluate the dose dependant impact of epothilone D, a brain penetrant MSA, on both immature and relatively mature mouse cortical neurons in vitro. We show that epothilone D reduces the viability, growth and complexity of immature cortical neurons in a dose dependant manner. Furthermore, in relatively mature cortical neurons, we demonstrate that while cellularly lethal doses of epothilone D cause cellular demise, low sub lethal doses can also affect mitochondrial transport over time. Our results reveal an underappreciated mitochondrial disruption over a wide range of epothilone D doses and reiterate the importance of understanding the dosage, timing and intended outcome of MSAs, with particular emphasis on brain penetrant MSAs being considered to target neurons in disease and trauma. Nature Publishing Group UK 2020-01-22 /pmc/articles/PMC6976590/ /pubmed/31969604 http://dx.doi.org/10.1038/s41598-020-57718-z Text en © The Author(s) 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Clark, J. A.
Chuckowree, J. A.
Dyer, M. S.
Dickson, T. C.
Blizzard, C. A.
Epothilone D alters normal growth, viability and microtubule dependent intracellular functions of cortical neurons in vitro
title Epothilone D alters normal growth, viability and microtubule dependent intracellular functions of cortical neurons in vitro
title_full Epothilone D alters normal growth, viability and microtubule dependent intracellular functions of cortical neurons in vitro
title_fullStr Epothilone D alters normal growth, viability and microtubule dependent intracellular functions of cortical neurons in vitro
title_full_unstemmed Epothilone D alters normal growth, viability and microtubule dependent intracellular functions of cortical neurons in vitro
title_short Epothilone D alters normal growth, viability and microtubule dependent intracellular functions of cortical neurons in vitro
title_sort epothilone d alters normal growth, viability and microtubule dependent intracellular functions of cortical neurons in vitro
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6976590/
https://www.ncbi.nlm.nih.gov/pubmed/31969604
http://dx.doi.org/10.1038/s41598-020-57718-z
work_keys_str_mv AT clarkja epothilonedaltersnormalgrowthviabilityandmicrotubuledependentintracellularfunctionsofcorticalneuronsinvitro
AT chuckowreeja epothilonedaltersnormalgrowthviabilityandmicrotubuledependentintracellularfunctionsofcorticalneuronsinvitro
AT dyerms epothilonedaltersnormalgrowthviabilityandmicrotubuledependentintracellularfunctionsofcorticalneuronsinvitro
AT dicksontc epothilonedaltersnormalgrowthviabilityandmicrotubuledependentintracellularfunctionsofcorticalneuronsinvitro
AT blizzardca epothilonedaltersnormalgrowthviabilityandmicrotubuledependentintracellularfunctionsofcorticalneuronsinvitro