A role for orexin in cytotoxic chemotherapy-induced fatigue.
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 6-24h after treatment during maximum fatigue/lethargy. CAF decreased orexin neuron activity as reflected by decreased nuclear cFos localization in orexin neurons 24h after treatment (p<0.05) and by decreased orexin-A in cerebrospinal fluid 16 h after treatment (p<0.001). Most importantly, we found that central administration of 1 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.
Oregon Health & Science University, Portland, OR 97239, United States. Electronic address: weymannk@ohsu.edu.
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Weymann
Oregon Health & Science University, Portland, OR 97239, United States; School of Nursing, MGH Institute of Health Professions, Boston, MA 02129, United States. Electronic address: ljwood@mghihp.edu.
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Wood
Oregon Health & Science University, Portland, OR 97239, United States. Electronic address: zhux@ohsu.edu.
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Zhu
Oregon Health & Science University, Portland, OR 97239, United States. Electronic address: marksd@ohsu.edu.
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Marks
D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity*; D001933:Brain Stem / Q000187:drug effects; D003520:Cyclophosphamide / Q000633:toxicity; D003603:Cytotoxins / Q000633:toxicity*; D004317:Doxorubicin / Q000633:toxicity; D004338:Drug Combinations; D004660:Encephalitis / Q000235:genetics; D005221:Fatigue / Q000139:chemically induced* / Q000378:metabolism; D005260:Female; D005472:Fluorouracil / Q000633:toxicity; D015870:Gene Expression; D007031:Hypothalamus / Q000187:drug effects; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009043:Motor Activity / Q000187:drug effects; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D009479:Neuropeptides / Q000378:metabolism; D000068797:Orexins; D051381:Rats; D017207:Rats, Sprague-Dawley
D000970:Antineoplastic Agents; D003603:Cytotoxins; D004338:Drug Combinations; D047908:Intracellular Signaling Peptides and Proteins; D009479:Neuropeptides; D000068797:Orexins; D004317:Doxorubicin; D003520:Cyclophosphamide; D005472:Fluorouracil
Activity; Cancer treatment; Cytotoxic chemotherapy; Fatigue; Hypothalamus; Inflammation; Orexin; Sickness behavior; Wakefulness