Characterization and reversal of Doxorubicin-mediated biphasic activation of ERK and persistent excitability in sensory neurons of Aplysia californica

Abstract Doxorubicin (DOX), a common chemotherapeutic agent, impairs synaptic plasticity. DOX also causes a persistent increase in basal neuronal excitability, which occludes serotonin-induced enhanced excitability. Therefore, we sought to characterize and reverse DOX-induced physiological changes a...

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Autores principales:	Harini Lakshminarasimhan, Brittany L. Coughlin, Amber S. Darr, John H. Byrne
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/9085c26eb1104bab9ba19e4f21ed459b
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spelling	oai:doaj.org-article:9085c26eb1104bab9ba19e4f21ed459b2021-12-02T16:06:30ZCharacterization and reversal of Doxorubicin-mediated biphasic activation of ERK and persistent excitability in sensory neurons of Aplysia californica10.1038/s41598-017-04634-42045-2322https://doaj.org/article/9085c26eb1104bab9ba19e4f21ed459b2017-07-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-04634-4https://doaj.org/toc/2045-2322Abstract Doxorubicin (DOX), a common chemotherapeutic agent, impairs synaptic plasticity. DOX also causes a persistent increase in basal neuronal excitability, which occludes serotonin-induced enhanced excitability. Therefore, we sought to characterize and reverse DOX-induced physiological changes and modulation of molecules implicated in memory induction using sensory neurons from the marine mollusk Aplysia californica. DOX produced two mechanistically distinct phases of extracellular signal-regulated kinase (ERK) activation, an early and a late phase. Inhibition of MEK (mitogen-activated protein kinase (MAPK)/ERK kinase) after DOX treatment reversed the late ERK activation. MEK inhibition during treatment enhanced the late ERK activation possibly through prolonged downregulation of MAPK phosphatase-1 (MKP-1). Unexpectedly, the late ERK activation negatively correlated with excitability. MEK inhibition during DOX treatment simultaneously enhanced the late activation of ERK and blocked the increase in basal excitability. In summary, we report DOX-mediated biphasic activation of ERK and the reversal of the associated changes in neurons, a potential strategy for reversing the deleterious effects of DOX treatment.Harini LakshminarasimhanBrittany L. CoughlinAmber S. DarrJohn H. ByrneNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-14 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Harini Lakshminarasimhan Brittany L. Coughlin Amber S. Darr John H. Byrne Characterization and reversal of Doxorubicin-mediated biphasic activation of ERK and persistent excitability in sensory neurons of Aplysia californica
description	Abstract Doxorubicin (DOX), a common chemotherapeutic agent, impairs synaptic plasticity. DOX also causes a persistent increase in basal neuronal excitability, which occludes serotonin-induced enhanced excitability. Therefore, we sought to characterize and reverse DOX-induced physiological changes and modulation of molecules implicated in memory induction using sensory neurons from the marine mollusk Aplysia californica. DOX produced two mechanistically distinct phases of extracellular signal-regulated kinase (ERK) activation, an early and a late phase. Inhibition of MEK (mitogen-activated protein kinase (MAPK)/ERK kinase) after DOX treatment reversed the late ERK activation. MEK inhibition during treatment enhanced the late ERK activation possibly through prolonged downregulation of MAPK phosphatase-1 (MKP-1). Unexpectedly, the late ERK activation negatively correlated with excitability. MEK inhibition during DOX treatment simultaneously enhanced the late activation of ERK and blocked the increase in basal excitability. In summary, we report DOX-mediated biphasic activation of ERK and the reversal of the associated changes in neurons, a potential strategy for reversing the deleterious effects of DOX treatment.
format	article
author	Harini Lakshminarasimhan Brittany L. Coughlin Amber S. Darr John H. Byrne
author_facet	Harini Lakshminarasimhan Brittany L. Coughlin Amber S. Darr John H. Byrne
author_sort	Harini Lakshminarasimhan
title	Characterization and reversal of Doxorubicin-mediated biphasic activation of ERK and persistent excitability in sensory neurons of Aplysia californica
title_short	Characterization and reversal of Doxorubicin-mediated biphasic activation of ERK and persistent excitability in sensory neurons of Aplysia californica
title_full	Characterization and reversal of Doxorubicin-mediated biphasic activation of ERK and persistent excitability in sensory neurons of Aplysia californica
title_fullStr	Characterization and reversal of Doxorubicin-mediated biphasic activation of ERK and persistent excitability in sensory neurons of Aplysia californica
title_full_unstemmed	Characterization and reversal of Doxorubicin-mediated biphasic activation of ERK and persistent excitability in sensory neurons of Aplysia californica
title_sort	characterization and reversal of doxorubicin-mediated biphasic activation of erk and persistent excitability in sensory neurons of aplysia californica
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/9085c26eb1104bab9ba19e4f21ed459b
work_keys_str_mv	AT harinilakshminarasimhan characterizationandreversalofdoxorubicinmediatedbiphasicactivationoferkandpersistentexcitabilityinsensoryneuronsofaplysiacalifornica AT brittanylcoughlin characterizationandreversalofdoxorubicinmediatedbiphasicactivationoferkandpersistentexcitabilityinsensoryneuronsofaplysiacalifornica AT ambersdarr characterizationandreversalofdoxorubicinmediatedbiphasicactivationoferkandpersistentexcitabilityinsensoryneuronsofaplysiacalifornica AT johnhbyrne characterizationandreversalofdoxorubicinmediatedbiphasicactivationoferkandpersistentexcitabilityinsensoryneuronsofaplysiacalifornica
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Characterization and reversal of Doxorubicin-mediated biphasic activation of ERK and persistent excitability in sensory neurons of Aplysia californica

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