National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, 9000 Rockville Pike, Bethesda, MD, 20892, USA.
National Heart, Lung, and Blood Institute, National Institutes of Health, 9000 Rockville Pike, Bethesda, MD, 20892, USA.
Behav Brain Res. 2019 Mar 15;360:255-261. doi: 10.1016/j.bbr.2018.12.011. Epub 2018 Dec 7.
Fatigue is a common symptom in many diseases and disorders and can reduce quality of life, yet lacks an adequate pharmacological intervention. To identify and develop such interventions, and to better understand fatigue, additional preclinical research is necessary. However, despite numerous mouse behavioral assays reportedly detecting fatigue-like behavior, the assumption that fatigue-like behavior is detected in many assays has not been validated through a cross-assay study. Thus, we modeled fatigue in mice by administering 5-fluorouracil, a chemotherapy drug known to cause fatigue in humans and fatigue-like behavior in mice, then evaluated its effects via voluntary wheel running activity (VWRA), locomotor activity in the open field test (OFT), immobility in the forced swim test (FST), and distance run in the treadmill fatigue test (TFT) and treadmill exercise capacity test. Additionally, taltirelin or methylphenidate was administered to alleviate fatigue-like behavior. As a result of 5-fluorouracil treatment, VWRA and the TFT were markedly reduced, indicating fatigue. The OFT, FST, and treadmill exercise capacity test, however, failed to detect fatigue-like behavior. Interestingly, both taltirelin and methylphenidate alleviated fatigue-like behavior in TFT. These data suggest that, of the current assays, only the TFT and VWRA should be expected to detect fatigue-like behavior. Moreover, this study provides additional evidence that taltirelin may provide a novel treatment for chemotherapy-induced fatigue and warrants further evaluation as an anti-fatigue therapeutic.
疲劳是许多疾病和障碍的常见症状，会降低生活质量，但目前缺乏有效的药物干预。为了找到并开发出这种干预措施，并更好地了解疲劳，还需要进行更多的临床前研究。然而，尽管有许多报道称小鼠行为检测可检测到疲劳样行为，但疲劳样行为在许多检测中被检测到的假设尚未通过交叉检测研究得到验证。因此，我们通过给小鼠注射氟尿嘧啶来模拟疲劳，氟尿嘧啶是一种已知会导致人类疲劳和小鼠疲劳样行为的化疗药物，然后通过自愿轮跑活动（VWRA）、旷场测试中的运动活动（OFT）、强迫游泳测试中的不动性（FST）以及跑步机疲劳测试（TFT）和跑步机运动能力测试来评估其效果。此外，还给予了他替瑞林或哌甲酯以缓解疲劳样行为。由于氟尿嘧啶的治疗，VWRA 和 TFT 明显减少，表明出现了疲劳。然而，OFT、FST 和跑步机运动能力测试未能检测到疲劳样行为。有趣的是，他替瑞林和哌甲酯都能缓解 TFT 中的疲劳样行为。这些数据表明，在目前的检测中，只有 TFT 和 VWRA 有望检测到疲劳样行为。此外，这项研究提供了更多证据表明，替瑞林可能为化疗引起的疲劳提供了一种新的治疗方法，值得进一步评估作为一种抗疲劳治疗方法。
