Institute for Behavioral Medicine Research, Ohio State University, Columbus, OH, USA; James Comprehensive Cancer Center and Solove Research Institute, Ohio State University, Columbus, OH, USA; Department of Neuroscience, Ohio State University, Columbus, OH, USA.
Institute for Behavioral Medicine Research, Ohio State University, Columbus, OH, USA.
Behav Brain Res. 2021 Feb 5;399:113041. doi: 10.1016/j.bbr.2020.113041. Epub 2020 Dec 3.
While chemotherapy remains a common cancer treatment, it is associated with debilitating side effects (e.g., anorexia, weight loss, and fatigue) that adversely affect patient quality of life and increase mortality. However, the mechanisms underlying taxane chemotherapy-induced side effects, and effective treatments to ameliorate them, are not well-established. Here, we tested the longitudinal relationship between a clinically-relevant paclitaxel regimen, inflammation, and sickness behaviors (loss of body mass, anorexia, fever, and fatigue) in adult, female mice. Furthermore, we sought to identify the extent to which voluntary exercise (wheel running) attenuates paclitaxel-induced sickness behaviors and underlying central pathways. Body mass and food intake decreased following six doses of chemotherapy treatment relative to vehicle controls, lasting less than 5 days after the last dose. Paclitaxel treatment also transiently decreased locomotion (open field test), voluntary wheel running, home-cage locomotion, and core body temperature without affecting motor coordination (rotarod task). Circulating interleukin (IL)-6 and hypothalamic Il1b gene expression remained elevated in chemotherapy-treated mice at least 3 days after the last dose. Exercise intervention did not ameliorate fatigue or inflammation, but hastened recovery from paclitaxel-induced weight loss. Body mass recovery was associated with the wheel running-induced recovery of body composition, paclitaxel-induced alterations to hypothalamic melanocortin signaling, and associated peripheral circulating hormones (ghrelin and leptin). The present findings demonstrate the benefits of exercise on faster recovery from paclitaxel-induced body mass loss and deficits in melanocortin signaling and suggests the development of therapies targeting the melanocortin pathway to reduce paclitaxel-induced weight loss.
虽然化疗仍然是一种常见的癌症治疗方法，但它会引起使人虚弱的副作用（例如厌食、体重减轻和疲劳），从而对患者的生活质量产生不利影响并增加死亡率。然而，紫杉烷类化疗引起副作用的机制以及改善这些副作用的有效治疗方法尚未得到很好的确定。在这里，我们测试了临床相关紫杉醇方案、炎症和疾病行为（体重减轻、厌食、发烧和疲劳）在成年雌性小鼠中的纵向关系。此外，我们试图确定自愿运动（跑步轮）在多大程度上减轻紫杉醇引起的疾病行为及其潜在的中枢途径。与载体对照相比，在接受六剂化疗治疗后，体重和食物摄入量下降，持续不到最后一剂后的 5 天。紫杉醇治疗还会短暂降低运动（旷场试验）、自愿跑步轮、笼内运动和核心体温，而不影响运动协调（旋转棒任务）。化疗后，循环白细胞介素（IL）-6 和下丘脑 Il1b 基因表达至少在最后一剂后 3 天仍升高。运动干预不能改善疲劳或炎症，但能加速紫杉醇引起的体重减轻的恢复。体重恢复与跑步轮引起的身体成分恢复、紫杉醇引起的黑皮质素信号改变以及相关的外周循环激素（胃饥饿素和瘦素）有关。目前的研究结果表明，运动对更快地从紫杉醇引起的体重减轻和黑皮质素信号受损中恢复有好处，并表明开发针对黑皮质素途径的疗法以减少紫杉醇引起的体重减轻是有意义的。
