A role for orexin in cytotoxic chemotherapy-induced fatigue.
A role for orexin in cytotoxic chemotherapy-induced fatigue.
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DOI：
10.1016/j.bbi.2013.11.003
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发表时间：
2014-03
期刊：
影响因子：
--
通讯作者：
Marks DL
中科院分区：
文献类型：
--
作者：
Weymann KB;Wood LJ;Zhu X;Marks DL
疲劳是肿瘤细胞毒性化疗治疗中最常见的症状。与细胞毒性化疗相关的外周炎症可能是疲劳的原因之一。细胞毒性化疗相关炎症导致疲劳行为的神经机制尚不清楚。这种知识的缺乏阻碍了减少或预防这一致残症状的干预措施的发展。感染引起的啮齿动物疲劳/嗜睡是通过抑制下丘脑增食欲素活性来调节的。食欲素对于保持清醒和积极的行为至关重要。虽然感染和细胞毒性化疗在某些症状上有所不同，但两者都会引起外周炎症和疲劳。基于这些相似性，我们假设细胞毒性化疗通过破坏食欲素神经元的活动而导致疲劳。我们发现，单剂量细胞毒性化疗鸡尾酒(环磷酰胺、阿霉素、5-氟尿嘧啶-CAF)可诱导小鼠和大鼠疲劳/昏睡，遥测测量的自主运动活动明显下降。CAF诱导炎性基因--IL-1R1(p<；0.001)、IL-6(p<；0.01)、肿瘤坏死因子α(p<；0.01)和单核细胞趋化蛋白-1(p<；0.05)--在最疲劳/昏睡状态下治疗6至24小时后在啮齿动物下丘脑中表达。CAF降低了增食欲素神经元的活性，表现为治疗24小时后增食欲素神经元胞核CFos定位减少(P<；0.001)和治疗16小时后脑脊液中增食欲素A的减少(P<；0.001)。最重要的是，我们发现中枢注射1-μ增食欲素-A恢复了CAF处理的大鼠的活动(p<；0.05)。这些结果表明，细胞毒性化疗诱导下丘脑炎症，抑制下丘脑增食欲素神经元活性在细胞毒性化疗所致的啮齿动物疲劳中起一定作用。
Fatigue is the most common symptom related to cytotoxic chemotherapeutic treatment of cancer. Peripheral inflammation associated with cytotoxic chemotherapy is likely a causal factor of fatigue. The neural mechanisms by which cytotoxic chemotherapy associated inflammation induces fatigue behavior are not known. This lack of knowledge hinders development of interventions to reduce or prevent this disabling symptom. Infection induced fatigue/lethargy in rodents is mediated by suppression of hypothalamic orexin activity. Orexin is critical for maintaining wakefulness and motivated behavior. Though there are differences between infection and cytotoxic chemotherapy in some symptoms, both induce peripheral inflammation and fatigue. Based on these similarities we hypothesized that cytotoxic chemotherapy induces fatigue by disrupting orexin neuron activity. We found that a single dose of a cytotoxic chemotherapy cocktail (cyclophosphamide, adriamycin, 5-fluorouracil—CAF) induced fatigue/lethargy in mice and rats as evidenced by a significant decline in voluntary locomotor activity measured by telemetry. CAF induced inflammatory gene expression—IL-1R1 (p<0.001), IL-6 (p<0.01), TNFα (p<0.01), and MCP-1 (p<0.05) —in the rodent hypothalamus 6 to 24 hours after treatment during maximum fatigue/lethargy. CAF decreased orexin neuron activity as reflected by decreased nuclear cFos localization in orexin neurons 24 hours after treatment (p<0.05) and by decreased orexin-A in cerebrospinal fluid 16 hours after treatment (p<0.001). Most importantly, we found that central administration of1 μg orexin-A restored activity in CAF-treated rats (p<0.05). These results demonstrate that cytotoxic chemotherapy induces hypothalamic inflammation and that suppression of hypothalamic orexin neuron activity has a causal role in cytotoxic chemotherapy-induced fatigue in rodents.
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影响因子：
3.7
作者：
Furutani N;Hondo M;Kageyama H;Tsujino N;Mieda M;Yanagisawa M;Shioda S;Sakurai T
通讯作者：
Sakurai T
DOI：
10.1073/pnas.1202526109
发表时间：
2012-09-25
影响因子：
11.1
作者：
Carter, Matthew E.;Brill, Julia;de Lecea, Luis
通讯作者：
de Lecea, Luis
影响因子：
15.1
作者：
Gaykema, Ronald P. A.;Goehler, Lisa E.
通讯作者：
Goehler, Lisa E.
影响因子：
2.7
作者：
Fenzl, Thomas;Romanowski, Christoph P. N.;Kimura, Mayumi
通讯作者：
Kimura, Mayumi
DOI：
10.1038/nrclinonc.2012.88
发表时间：
2012-05-29
期刊：
Nature reviews. Clinical oncology
影响因子：
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作者：
通讯作者：
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