Screening study of anti-emetics to improve GDF15-induced malaise and anorexia: Implications for emesis control

Abstract

Considerable preclinical and clinical attention has focused on the food intake and body weight suppressive effects of growth differentiation factor 15 (GDF15) and its elevated blood levels as a consequence of disease states and disease treatment therapeutics. We have previously reported that exogenous administration of GDF15 induces anorexia through nausea and emesis in multiple species. Importantly, GDF15 signaling as a meditator of chemotherapy-induced anorexia and emesis has recently been demonstrated in both murine and nonhuman primate models. The mechanism, however, by which GDF15 induces malaise and the utility of existing therapeutic targets to counteract its effects remain largely unknown. Using a dose of GDF15 that mimics stimulated levels following chemotherapy administration and reliably induces malaise, we sought to screen anti-emetics that represent distinct pharmacotherapeutic classes hypothesized to reduce GDF15-induced effects in rats. Strikingly, our results showed that none of the tested compounds were effective at preventing GDF15-induced malaise. These results illustrate the complexity of GDF15 signaling mechanism and may have important implications for medical conditions characterized by elevated GDF15 levels and incomplete symptom control, such as chemotherapy-induced nausea and vomiting.

Keywords: Anorexia; Anti-emetics; Chemotherapy; Emesis; GDF15; MIC-1; Nausea; Side effects.

Fig. 1.

First-line anti-emetics used in the oncology field failed to suppress GDF15-induced malaise and anorexia. Ondansetron pre-treatment (1 mg/kg) failed to attenuate kaolin consumption (A) and anorexia (B) induced by GDF15 (20 μg/kg, n = 12/group). Despite showing a trend, metoclopramide administration (2.5 mg/kg, n = 15/group) did not significantly attenuate GDF15-induced malaise (C) and anorexia (D). Treatment with the anti-inflammatory drug dexamethasone (1 mg/kg, n = 12/group) did not prevent GDF15-induced effects on food intake (E) nor on kaolin intake (F). Dimenhydrinate pre-treatment (5 mg/kg, n = 12/group) failed to attenuate GDF15-induced kaolin intake (G) and did not affect food intake (H). All data expressed as mean ± SEM and analyzed with 2 × 2 RM-ANOVAs followed by Tukey’s post hoc tests. Means with different letters are significantly different from each other (P < 0.05).

Fig. 2.

Various compounds studied in the context of emesis, nausea, and anorexia failed to attenuate GDF15-induced effects. Pre-treatment with the GLP-1R antagonist Exendin-9 (1 mg/kg) failed to attenuate pica (A) and anorexia (B) induced by GDF15 (20 μg/kg, n = 13/group). Despite stimulating feeding, Anamorelin (5 mg/kg, n = 14/group) failed to significantly attenuate GDF15-induced kaolin consumption in rats (C-D). Treatment with the long-acting cannabinoid 1 receptor agonist WIN-55 (1 mg/kg, n = 15/group) did not prevent GDF15-induced effects on kaolin (E) and food (F) intake. The selective CCK-1 receptor antagonist Devazepide (0.5 mg/kg, n = 12/group) did not affect GDF15-induced kaolin intake at any time point measured (G) and was ineffective at preventing anorexia at 24 h (H). All data expressed as mean ± SEM and analyzed with 2 × 2 RM-ANOVAs followed by Tukey’s post hoc tests. Means with different letters are significantly different from each other (P < 0.05).