Document Type


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Oregon Health & Science University


Background 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. However, 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 signaling. Orexin is critical for maintaining wakefulness and motivated behavior. Although there are differences between infection and cytotoxic chemotherapy in some symptoms, both induce peripheral inflammation and fatigue. These similarities formed the basis of my hypothesis that cytotoxic chemotherapy induces fatigue by disrupting orexin signaling. Methods A cytotoxic chemotherapy cocktail (cyclophosphamide, adriamycin, 5-fluorouracil—CAF) commonly used to treat breast cancer was administered to mice and rats. Fatigue was measured by a decrease in voluntary ambulatory and wheel running activity, measured by telemetry. Reverse transcription real-time PCR was used to measure inflammatory gene expression in the hypothalamus and brainstem. Hypothalamic orexin neuron activity was determined with immunohistochemical examination of nuclear cFos localization and measurement of cerebrospinal fluid levels of orexin-A. Exogenous orexin-A neuropeptide was administered through a vii surgically implanted brain catheter. Results A single dose of CAF induced fatigue in mice and rats as evidenced by a significant decline in voluntary locomotor activity. CAF induced inflammatory gene expression—IL-1R1 (p




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