Ibuprofen ameliorates fatigue- and depressive-like behavior in tumor-bearing mice

Abstract

Aims: Cancer-related fatigue (CRF) is often accompanied by depressed mood, both of which reduce functional status and quality of life. Research suggests that increased expression of pro-inflammatory cytokines is associated with skeletal muscle wasting and depressive- and fatigue-like behaviors in rodents and cancer patients. We have previously shown that treatment with ibuprofen, a nonsteroidal anti-inflammatory drug, preserved muscle mass in tumor-bearing mice. Therefore, the purpose of the present study was to determine the behavioral effects of ibuprofen in a mouse model of CRF.

Main methods: Mice were injected with colon-26 adenocarcinoma cells and treated with ibuprofen (10mg/kg) in the drinking water. Depressive-like behavior was determined using the forced swim test (FST). Fatigue-like behaviors were determined using voluntary wheel running activity (VWRA) and grip strength. The hippocampus, gastrocnemius muscle, and serum were collected for cytokine analysis.

Key findings: Tumor-bearing mice showed depressive-like behavior in the FST, which was not observed in mice treated with ibuprofen. VWRA and grip strength declined in tumor-bearing mice, and ibuprofen attenuated this decline. Tumor-bearing mice had decreased gastrocnemius muscle mass and increased expression of IL-6, MAFBx and MuRF mRNA, biomarkers of protein degradation, in the muscle. Expression of IL-1β and IL-6 was also increased in the hippocampus. Treatment with ibuprofen improved muscle mass and reduced cytokine expression in both the muscle and hippocampus of tumor-bearing mice.

Significance: Ibuprofen treatment reduced skeletal muscle wasting, inflammation in the brain, and fatigue- and depressive-like behavior in tumor-bearing mice. Therefore, ibuprofen warrants evaluation as an adjuvant treatment for CRF.

Keywords: Cancer; Depression; Fatigue; Ibuprofen; Neuroinflammation.

Figure 1. Ibuprofen ameliorated fatigue-and depressive-like behaviors in tumor-bearing mice

Control and tumor-bearing mice were treated with ibuprofen (10 mg/kg/day) in the drinking water. A) Immobility in the forced swim test (FST) was determined on day 13 of tumor growth. B) Voluntary wheel running activity (VWRA) was determined before tumor cell injection and again at days 7, 14, and 20. Data are expressed as percentage of baseline. Data were analyzed using two-way ANOVA and post hoc t-tests for significant main effects: *p<0.05 from control-vehicle, # p<0.05 from tumor-vehicle..

Figure 2. Ibuprofen restored grip strength in tumor-bearing mice

Control and tumor-bearing mice were treated with ibuprofen (10 mg/kg/day) in the drinking water. A) Absolute grip strength was determined before tumor cell injection and again at day 11 and 19. B) At day 20, grip strength was normalized to body weight. Data were analyzed using two-way ANOVA and post hoc t-tests for significant main effects: *p<0.05 from control-vehicle, # p<0.05 from tumor-vehicle.

Figure 3. Ibuprofen decreased systemic inflammation and muscle wasting in tumor-bearing mice

Control and tumor-bearing mice were treated with ibuprofen (10 mg/kg/day) in the drinking water. A) Spleen weight, B) plasma IL-6, C) tumor mass, and D) gastrocnemius muscle mass was determined at day 21. Gastrocnemius mRNA expression of E) MuRF, F) MAFBx, and G) IL-6 mRNA expression was determined at day 21. Data were analyzed using two-way ANOVA and post hoc t-tests for significant main effects: *p<0.05 from control-vehicle, #p<0.05 from tumor-vehicle.

Figure 4. Ibuprofen attenuated neuroinflammation in tumor-bearing mice

Control and tumor-bearing mice were treated with ibuprofen (10mg/kg/day) in the drinking water. On day 21, the brain was collected and the hippocampus was dissected. A) IL-1β and B) IL-6 mRNA expression was determined. Data were analyzed using two-way ANOVA and post hoc t-tests for significant main effects: *p<0.05 from control-vehicle, # p<0.05 from tumor-vehicle..