title: Dexamethasone Chemotherapy Does Not Disrupt Orexin Signaling.
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.
authors.affiliation: Division of Pediatric Hematology-Oncology, Doernbecher Children's Hospital/Oregon Health & Science University, Portland, Oregon, United States of America.
authors.forename: David E
authors.initials: DE
authors.lastname: Kram
authors.affiliation: Papé Family Pediatric Research Institute, Oregon Health & Science University, Portland, Oregon, United States of America.
authors.forename: Stephanie M
authors.initials: SM
authors.lastname: Krasnow
authors.affiliation: Papé Family Pediatric Research Institute, Oregon Health & Science University, Portland, Oregon, United States of America.
authors.forename: Peter R
authors.initials: PR
authors.lastname: Levasseur
authors.affiliation: Papé Family Pediatric Research Institute, Oregon Health & Science University, Portland, Oregon, United States of America.
authors.forename: Xinxia
authors.initials: X
authors.lastname: Zhu
authors.affiliation: Division of Pediatric Hematology-Oncology, Doernbecher Children's Hospital/Oregon Health & Science University, Portland, Oregon, United States of America.
authors.forename: Linda C
authors.initials: LC
authors.lastname: Stork
authors.affiliation: Papé Family Pediatric Research Institute, Oregon Health & Science University, Portland, Oregon, United States of America.
authors.forename: Daniel L
authors.identifier: http://orcid.org/0000-0003-2675-7047
authors.initials: DL
authors.lastname: Marks
mesh_terms: D000293:Adolescent; D000818:Animals; D002648:Child; D002675:Child, Preschool; D003907:Dexamethasone / Q000008:administration & dosage / Q000009:adverse effects; D005260:Female; D006801:Humans; D007031:Hypothalamus / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D051379:Mice; D009474:Neurons / Q000378:metabolism*; D000068797:Orexins / Q000378:metabolism*; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects*; D012893:Sleep Wake Disorders / Q000139:chemically induced / Q000378:metabolism / Q000503:physiopathology
chemical_list: D000068797:Orexins; D003907:Dexamethasone