Kram David E, Krasnow Stephanie M, Levasseur Peter R, Zhu Xinxia, Stork Linda C, Marks Daniel L
Division of Pediatric Hematology-Oncology, Doernbecher Children's Hospital/Oregon Health & Science University, Portland, Oregon, United States of America.
Papé Family Pediatric Research Institute, Oregon Health & Science University, Portland, Oregon, United States of America.
PLoS One. 2016 Dec 20;11(12):e0168731. doi: 10.1371/journal.pone.0168731. eCollection 2016.
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.
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.
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.
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.
对于接受类固醇化疗治疗小儿急性淋巴细胞白血病（ALL）的儿童而言，类固醇诱导的睡眠障碍是一种常见且令人极为苦恼的病症。睡眠障碍会对整体生活质量、神经发育、记忆巩固和伤口愈合产生负面影响。下丘脑食欲素神经元是有影响力的促觉醒神经元，食欲素信号传导紊乱会导致异常睡眠行为。一类新型药物——食欲素受体拮抗剂，可能是治疗因食欲素能输出增加引起的睡眠障碍的一个有趣选择。我们的目的是研究ALL治疗剂量的皮质类固醇对啮齿动物和接受儿童ALL治疗的儿童的食欲素系统的影响。
我们给啮齿动物反复注射地塞米松，并与对照组相比测量反应性食欲素神经活动。在2014 - 2016年根据儿童肿瘤学组（COG）诱导治疗方案接受地塞米松治疗的新诊断标准风险B细胞ALL患儿中，我们收集了类固醇治疗前和治疗期间匹配的脑脊液样本，并测量了类固醇对脑脊液食欲素浓度的影响。
在啮齿动物中，所有食欲素信号标记物，包括食欲素神经输出和食欲素受体表达，在地塞米松作用下均得以保留。此外，我们未检测到接受地塞米松治疗的儿童在治疗前和治疗期间脑脊液食欲素浓度存在差异。
我们的结果表明，在高剂量地塞米松作用下，啮齿动物和人类的食欲素生理学在很大程度上得以保留。我们在实验模型中获得的数据未能证明食欲素途径破坏在类固醇诱导的睡眠障碍中起因果作用。
