Dexamethasone chemotherapy does not disrupt orexin signaling

David E. Kram, Stephanie Krasnow, Peter R. Levasseur, Xinxia Zhu, Linda Stork, Daniel Marks

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish (US)
Article numbere0168731
JournalPLoS One
Volume11
Issue number12
DOIs
StatePublished - Dec 1 2016

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Chemotherapy
dexamethasone
Dexamethasone
drug therapy
lymphocytic leukemia
steroids
sleep
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Drug Therapy
Steroids
Rodentia
Sleep
rodents
Neurons
neurons
Orexin Receptors
human physiology
Drug Receptors
therapeutics
receptors

ASJC Scopus subject areas

  • Medicine(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

Dexamethasone chemotherapy does not disrupt orexin signaling. / Kram, David E.; Krasnow, Stephanie; Levasseur, Peter R.; Zhu, Xinxia; Stork, Linda; Marks, Daniel.

In: PLoS One, Vol. 11, No. 12, e0168731, 01.12.2016.

Research output: Contribution to journalArticle

Kram, David E. ; Krasnow, Stephanie ; Levasseur, Peter R. ; Zhu, Xinxia ; Stork, Linda ; Marks, Daniel. / Dexamethasone chemotherapy does not disrupt orexin signaling. In: PLoS One. 2016 ; Vol. 11, No. 12.
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