Modulation of Central Fatigue‐Associated Neural Factors by Cancer Chemotherapy Agent 5‐Fluorouracil

Abstract

A dearth of studies has attempted to elucidate the etiology of cancer‐related fatigue (CRF). The purpose was to determine effects of chemotherapy agent 5‐fluorouracil (5FU), known to induce CRF, on cytokines and neurotransmitter systems in distinct regions of the brain that are implicated in the development of central fatigue.MethodsMice were intraperitoneally injected with 5FU or saline (placebo) for 5 days and sacrificed 12‐hrs (post‐1) or 9 days (post‐9) after the last injection.Results5FU induced a significant increase in mRNA expression of IL‐1β on post‐9 (p < 0.05) in the brainstem and cerebellum and 5‐HT2A receptor in the cerebellum on post‐1(39%, p < 0.05). There was a trend for elevated mRNA expression of dopamine D2 receptor on post‐1 (6% and 16%) and post‐9 (32% and 22%) in the brainstem and cerebellum respectively. The cerebellum showed a slight increase in mRNA expression of 5‐HT1A receptor on post‐1 (30%) and post‐9 (21%). Our data revealed positive correlations among 5‐HT1A/B, 5‐HT2A and D2 receptors. MCP‐1 mRNA expression was positively correlated with IL‐1β, 5‐HT1B and 5‐HT2A in the brainstem (p < 0.05).ConclusionOur results are the first to show that 5FU have an impact on IL‐1β and serotonin and dopamine receptors in the brainstem and/or cerebellum which provide strong evidence for current theories of the development of central fatigue and, therefore, for CRF induced by 5FU.