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Published on: August 25, 2019
Dexamethasone Chemotherapy Does Not Disrupt Orexin Signaling
David E Kram1, Stephanie M Krasnow2, Peter R Levasseur2
1Division of Pediatric Hematology-Oncology, Doernbecher Children's Hospital/Oregon Health & Science University, Portland, Oregon, United States of America.
Insights
High-dose corticosteroids used in acute lymphoblastic leukemia (ALL) treatment do not disrupt the orexin system in rodents or children. This suggests the orexin pathway is not the cause of steroid-induced sleep disturbances in pediatric ALL patients.
Area of Science:
- Neuroscience
- Endocrinology
- Pediatric Oncology
Background:
- Steroid-induced sleep disturbance is a common side effect in pediatric acute lymphoblastic leukemia (ALL) patients undergoing chemotherapy.
- Sleep disruption negatively impacts quality of life, neurodevelopment, and healing.
- Orexin neurons promote wakefulness, and their signaling is crucial for normal sleep behavior.
Purpose of the Study:
- To investigate the impact of corticosteroid treatment doses on the orexin system in rodents and children with ALL.
- To determine if the orexin pathway is implicated in steroid-induced sleep disturbances.
Main Methods:
- Rodents received repeated dexamethasone injections; orexin neural activity was measured.
- Cerebrospinal fluid (CSF) samples were collected from pediatric ALL patients before and during dexamethasone therapy.
- CSF orexin concentrations were analyzed to assess steroid impact.
Main Results:
- Orexin signaling markers, including neural output and receptor expression, remained unchanged in rodents treated with dexamethasone.
- No significant difference was observed in CSF orexin concentrations in children before and during dexamethasone therapy.
- Rodent and human orexin physiology appears largely preserved under high-dose dexamethasone.
Conclusions:
- High-dose dexamethasone does not significantly alter orexin physiology in rodents or humans.
- The orexin pathway is unlikely to be the primary cause of sleep disturbances associated with steroid treatment in pediatric ALL.
- Orexin receptor antagonists may not be a suitable therapeutic strategy for this specific sleep disorder.
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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