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Dexamethasone Chemotherapy Does Not Disrupt Orexin Signaling

BACKGROUND: Steroid-induced sleep disturbance is a common and highly distressing morbidity for children receiving steroid chemotherapy for the treatment of pediatric acute lymphoblastic leukemia (ALL). Sleep disturbance can negatively impact overall quality of life, neurodevelopment, memory consolid...

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Autores principales: Kram, David E., Krasnow, Stephanie M., Levasseur, Peter R., Zhu, Xinxia, Stork, Linda C., Marks, Daniel L.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5173249/
https://www.ncbi.nlm.nih.gov/pubmed/27997622
http://dx.doi.org/10.1371/journal.pone.0168731
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author Kram, David E.
Krasnow, Stephanie M.
Levasseur, Peter R.
Zhu, Xinxia
Stork, Linda C.
Marks, Daniel L.
author_facet Kram, David E.
Krasnow, Stephanie M.
Levasseur, Peter R.
Zhu, Xinxia
Stork, Linda C.
Marks, Daniel L.
author_sort Kram, David E.
collection PubMed
description BACKGROUND: Steroid-induced sleep disturbance is a common and highly distressing morbidity for children receiving steroid chemotherapy for the treatment of pediatric acute lymphoblastic leukemia (ALL). Sleep disturbance can negatively impact overall quality of life, neurodevelopment, memory consolidation, and wound healing. Hypothalamic orexin neurons are influential wake-promoting neurons, and disturbances in orexin signaling leads to abnormal sleep behavior. A new class of drug, the orexin receptor antagonists, could be an intriguing option for sleep disorders caused by increased orexinergic output. Our aim was to examine the impact of ALL treatment doses of corticosteroids on the orexin system in rodents and in children undergoing treatment for childhood ALL. METHODS: We administered repeated injections of dexamethasone to rodents and measured responsive orexin neural activity compared to controls. In children with newly diagnosed standard risk B-cell ALL receiving dexamethasone therapy per Children’s Oncology Group (COG) induction therapy from 2014–2016, we collected pre- and during-steroids matched CSF samples and measured the impact of steroids on CSF orexin concentration. RESULTS: In both rodents, all markers orexin signaling, including orexin neural output and orexin receptor expression, were preserved in the setting of dexamethasone. Additionally, we did not detect a difference in pre- and during-dexamethasone CSF orexin concentrations in children receiving dexamethasone. CONCLUSIONS: Our results demonstrate that rodent and human orexin physiology is largely preserved in the setting of high dose dexamethasone. The data obtained in our experimental model fail to demonstrate a causative role for disruption of the orexin pathway in steroid-induced sleep disturbance.
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spelling pubmed-51732492017-01-04 Dexamethasone Chemotherapy Does Not Disrupt Orexin Signaling Kram, David E. Krasnow, Stephanie M. Levasseur, Peter R. Zhu, Xinxia Stork, Linda C. Marks, Daniel L. PLoS One Research Article BACKGROUND: Steroid-induced sleep disturbance is a common and highly distressing morbidity for children receiving steroid chemotherapy for the treatment of pediatric acute lymphoblastic leukemia (ALL). Sleep disturbance can negatively impact overall quality of life, neurodevelopment, memory consolidation, and wound healing. Hypothalamic orexin neurons are influential wake-promoting neurons, and disturbances in orexin signaling leads to abnormal sleep behavior. A new class of drug, the orexin receptor antagonists, could be an intriguing option for sleep disorders caused by increased orexinergic output. Our aim was to examine the impact of ALL treatment doses of corticosteroids on the orexin system in rodents and in children undergoing treatment for childhood ALL. METHODS: We administered repeated injections of dexamethasone to rodents and measured responsive orexin neural activity compared to controls. In children with newly diagnosed standard risk B-cell ALL receiving dexamethasone therapy per Children’s Oncology Group (COG) induction therapy from 2014–2016, we collected pre- and during-steroids matched CSF samples and measured the impact of steroids on CSF orexin concentration. RESULTS: In both rodents, all markers orexin signaling, including orexin neural output and orexin receptor expression, were preserved in the setting of dexamethasone. Additionally, we did not detect a difference in pre- and during-dexamethasone CSF orexin concentrations in children receiving dexamethasone. CONCLUSIONS: Our results demonstrate that rodent and human orexin physiology is largely preserved in the setting of high dose dexamethasone. The data obtained in our experimental model fail to demonstrate a causative role for disruption of the orexin pathway in steroid-induced sleep disturbance. Public Library of Science 2016-12-20 /pmc/articles/PMC5173249/ /pubmed/27997622 http://dx.doi.org/10.1371/journal.pone.0168731 Text en © 2016 Kram et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Kram, David E.
Krasnow, Stephanie M.
Levasseur, Peter R.
Zhu, Xinxia
Stork, Linda C.
Marks, Daniel L.
Dexamethasone Chemotherapy Does Not Disrupt Orexin Signaling
title Dexamethasone Chemotherapy Does Not Disrupt Orexin Signaling
title_full Dexamethasone Chemotherapy Does Not Disrupt Orexin Signaling
title_fullStr Dexamethasone Chemotherapy Does Not Disrupt Orexin Signaling
title_full_unstemmed Dexamethasone Chemotherapy Does Not Disrupt Orexin Signaling
title_short Dexamethasone Chemotherapy Does Not Disrupt Orexin Signaling
title_sort dexamethasone chemotherapy does not disrupt orexin signaling
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5173249/
https://www.ncbi.nlm.nih.gov/pubmed/27997622
http://dx.doi.org/10.1371/journal.pone.0168731
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