Taltirelin, a thyrotropin-releasing hormone analog, alleviates fatigue in healthy mice and chemotherapy-induced fatigue mouse models

Authors

• JP Dougherty
• MJ Cullen
• DA Springer
• MC Gershengorn

Abstract

Most cancer patients experience cancer-related fatigue (CRF), which can markedly reduce quality of life. Unfortunately, CRF has no broadly-effective drug treatment. Thyrotropin-releasing hormone (TRH) has been suggested as a potential CRF treatment, but is limited by a short half-life and poor blood-brain barrier penetration. To test if TRH receptor activation could alleviate fatigue in mouse models, we used a TRH analog, taltirelin (TAL), which has a longer half-life and more readily crosses the blood-brain barrier. We used two mouse assays of fatigue-like behavior: voluntary running wheel activity (VWRA) and the treadmill fatigue test (TFT). To model CRF, we used mouse chemotherapy-induced fatigue (CIF) models. Mice were injected with 5-fluorouracil (5-FU), a chemotherapy drug that causes fatigue. Because CRF severity varies, 5-FU was administered to induce moderate (cumulative 8-day dose: 140 mg/kg) or severe fatigue (cumulative 5-day dose: 300 mg/kg). Moderate 5-FU treatment reduced wheel running by approximately 40 percent for up to 2 weeks and reduced distance run in the TFT. When 5-FU was given to induce severe fatigue, mice displayed weight loss, near-complete reduction in wheel running, and markedly reduced distance run in the TFT. Remarkably, TAL treatment fully reversed the effect of 5-FU treatment in the TFT in both CIF models and reduced the duration of fatigue-like behavior in moderately-fatigued mice by more than half. Additionally, TAL was effective when given orally and was consistently efficacious with repeated treatment. Our data demonstrate that TAL may provide a novel treatment for CIF and warrants further evaluation.

Scientific Focus Area: Molecular Pharmacology

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