Taltirelin alleviates fatigue-like behavior in mouse models of cancer-related fatigue

Abstract

Fatigue affects most cancer patients and has numerous potential causes, including cancer itself and cancer treatment. Cancer-related fatigue (CRF) is not relieved by rest, can decrease quality of life, and has no FDA-approved therapy. Thyrotropin-releasing hormone (TRH) has been proposed as a potential novel treatment for CRF, but its efficacy against CRF remains largely untested. Thus, we tested the TRH analog, taltirelin (TAL), in mouse models of CRF. To model fatigue, we used a mouse model of chemotherapy, a mouse model of radiation therapy, and mice bearing colon 26 carcinoma tumors. We used the treadmill fatigue test to assess fatigue-like behavior after treatment with TAL. Additionally, we used wild-type and TRH receptor knockout mice to determine which TRH receptor was necessary for the actions of TAL. Tumor-bearing mice displayed muscle wasting and all models caused fatigue-like behavior, with mice running a shorter distance in the treadmill fatigue test than controls. TAL reversed fatigue-like behavior in all three models and the mouse TRH1 receptor was necessary for the effects of TAL. These data suggest that TAL may be useful in alleviating fatigue in all cancer patients and provide further support for evaluating TAL as a potential therapy for CRF in humans.

Evaluation of the effects of chemotherapy-induced fatigue and pharmacological interventions in multiple mouse behavioral assays

“…Research toward these goals requires preclinical models of fatigue, preclinical assays to measure fatigue-like behavior, and knowledge that fatigue-like behavior is being detected by the assay. Numerous models of fatigue are in use, including a variety of CRF models [6][7][8][9] as well as inflammation-induced fatigue models intended to recapitulate aspects of other disorders, such as CFS/ME and SS [10][11][12]. Although these models cannot fully replicate human fatigue, they can provide valuable tools for understanding potential causes of fatigue and identifying potential biomarkers and therapeutics.…”

“…We focused on a single mouse model of fatigue, inducing fatigue via injections of a cytotoxic chemotherapy drug, 5-fluorouracil . This model was selected because prior studies have shown it induces fatigue-like behavior as measured by VWRA [16,29] and, at a lower dose, 5-FU also induces fatigue-like behavior in the TFT [6]. Additionally, we tested two potential anti-fatigue therapeutics, taltirelin (TAL) and methylphenidate (MPH), to determine if any observed fatigue-like behavior was alleviated.…”

“…administration of a 0.5 or 1.5 mg dose for this effect. TAL was selected for the current study because it has a more favorable pharmacokinetic profile than TRH and alleviates fatigue-like behavior, as determined using the TFT, in mouse models of chemotherapy-, irradiation-, or tumor-induced fatigue [6]. MPH is a psychostimulant that alleviates CRF in some patients in the clinic [31], but there is not a consistent anti-fatigue effect across patient populations.…”

Comparing passive measures of fatigue-like behavior in mice

“…Although fatigue is considered to be a multidimensional behavior, it is mostly manifested as a decline in physical function and daily activity 6 . Much of the published work on mouse models of fatigue focuses on cancer-related fatigue, which can be induced by tumor growth 7 – 10 , chemotherapy 10 – 15 , or radiation 10 , 16 , 17 . Other published studies induce fatigue using lipopolysaccharide 18 or exercise 19 , 20 .…”

“…In clinical studies, fatigue is typically determined by self-reports and questionnaires, and rarely using behavioral or physical measurements 2 . In contrast, with preclinical mouse models investigators have published quite a few behavioral measures of physical activity to measure fatigue, including: running wheels 7 – 9 , 11 , 12 , 14 – 17 , 20 , 21 ; home cage monitoring using video 7 , 8 , 18 , telemetry 11 , or cages with light beams/sensors 20 ; treadmills 10 , 19 , 21 ; forced swim 8 , 9 ; and open field 12 . However, there are no standards for which methods should be considered reliable indicators of fatigue.…”