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

Abstract 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 s...

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Autores principales:	J. A. Clark, J. A. Chuckowree, M. S. Dyer, T. C. Dickson, C. A. Blizzard
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2020
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/4bdba742d30049b0b11e7bf02dd84e9c
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spelling	oai:doaj.org-article:4bdba742d30049b0b11e7bf02dd84e9c2021-12-02T15:23:48ZEpothilone D alters normal growth, viability and microtubule dependent intracellular functions of cortical neurons in vitro10.1038/s41598-020-57718-z2045-2322https://doaj.org/article/4bdba742d30049b0b11e7bf02dd84e9c2020-01-01T00:00:00Zhttps://doi.org/10.1038/s41598-020-57718-zhttps://doaj.org/toc/2045-2322Abstract 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.J. A. ClarkJ. A. ChuckowreeM. S. DyerT. C. DicksonC. A. BlizzardNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 10, Iss 1, Pp 1-14 (2020)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q J. A. Clark J. A. Chuckowree M. S. Dyer T. C. Dickson C. A. Blizzard Epothilone D alters normal growth, viability and microtubule dependent intracellular functions of cortical neurons in vitro
description	Abstract 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	article
author	J. A. Clark J. A. Chuckowree M. S. Dyer T. C. Dickson C. A. Blizzard
author_facet	J. A. Clark J. A. Chuckowree M. S. Dyer T. C. Dickson C. A. Blizzard
author_sort	J. A. Clark
title	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_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_sort	epothilone d alters normal growth, viability and microtubule dependent intracellular functions of cortical neurons in vitro
publisher	Nature Portfolio
publishDate	2020
url	https://doaj.org/article/4bdba742d30049b0b11e7bf02dd84e9c
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Epothilone D alters normal growth, viability and microtubule dependent intracellular functions of cortical neurons in vitro

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