Dexamethasone Chemotherapy Does Not Disrupt Orexin Signaling

Abstract

BackgroundSteroid-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.MethodsWe 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.ResultsIn 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.ConclusionsOur 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.

Involvement of the Orexinergic System in Cancer: Antitumor Strategies and Future Perspectives

“…Dexamethasone chemotherapy did not block the orexinergic signaling in children with acute lymphoblastic leukemia; the same finding was observed in rodents [84]. Thus, a high dose of dexamethasone did not disrupt the human orexin physiology and this system was well preserved (e.g., OXR expression and neural output).…”

“…Dexamethasone chemotherapy did not block the orexinergic signaling. [84,85] Adrenocortical adenoma Prepro-orexin mRNA, orexin A (not orexin B) and OXR1/OXR2 upregulation. Orexin A, but not orexin B, augmented normal/adrenocortical adenoma cell proliferation.…”

Dexamethasone induces sleep disturbance in a dose-dependent manner in mice

“…The activity of each neural system under steroid administration is not fully understood, but several pieces of evidence indicate that some neurons and neurotransmitters are affected, and others are not affected by DXM administration. Regarding orexin neurons, which are known as the principal component of the wakefulness-promoting system [ 10 , 21 , 22 ], a previous study showed that the concentration of orexin protein concentration in the hypothalamus does not change even under DXM administration (5 d at a concentration of 1.5 mg/kg); this indicates that the output of the orexin neuron does not change following DXM administration in mice [ 23 ]. Another study shows that intramuscular DXM administration (7 d at a concentration of 1 mg/kg) increased noradrenaline and decreased adrenaline levels and did not alter the serotonin level of the pineal-paraphyseal complex in Lissemys punctata punctata [ 24 ].…”

“…under DXM administration (5 d at a concentration of 1.5 mg/kg); this indicates that the output of the orexin neuron does not change following DXM administration in mice [23]. Another study shows that intramuscular DXM administration (7 d at a concentration of 1 mg/kg) increased noradrenaline and decreased adrenaline levels and did not alter the serotonin level of the pineal-paraphyseal complex in Lissemys punctata punctata [24].…”

Steroid-Induced Sleep Disturbance and Delirium: A Focused Review for Critically Ill Patients

“…However, this effect was specifically evaluated in a recent study in children with acute lymphoblastic leukemia, which showed that cerebral spinal fluid orexin levels (SD) were not significantly different from baseline after dexamethasone administration: 574 (26.6) pg/mL vs 580 (126.1) pg/mL; P = .8. 45…”