GIP receptor agonism blocks chemotherapy-induced nausea and vomiting

Abstract

Objective: Nausea and vomiting remain life-threatening obstacles to successful treatment of chronic diseases, despite a cadre of available antiemetic medications. Our inability to effectively control chemotherapy-induced nausea and vomiting (CINV) highlights the need to anatomically, molecularly, and functionally characterize novel neural substrates that block CINV.

Methods: Behavioral pharmacology assays of nausea and emesis in 3 different mammalian species were combined with histological and unbiased transcriptomic analyses to investigate the beneficial effects of glucose-dependent insulinotropic polypeptide receptor (GIPR) agonism on CINV.

Results: Single-nuclei transcriptomics and histological approaches in rats revealed a topographical, molecularly distinct, GABA-ergic neuronal population in the dorsal vagal complex (DVC) that is modulated by chemotherapy but rescued by GIPR agonism. Activation of DVCGIPR neurons substantially decreased behaviors indicative of malaise in cisplatin-treated rats. Strikingly, GIPR agonism blocks cisplatin-induced emesis in both ferrets and shrews.

Conclusion: Our multispecies study defines a peptidergic system that represents a novel therapeutic target for the management of CINV, and potentially other drivers of nausea/emesis.

Keywords: Antiemetic; Chemotherapy; Diabetes; Incretin; Obesity; Vomiting.

Figure 1

GIPR agonism attenuates nausea and emesis in 3 different mammalian species. A) GIPR agonism (GIP-532, 3 nmol/kg, SC) blocks retching induced by the chemotherapeutic agent cisplatin (10 mg/kg, IP) in ferrets (n = 5/group). B) While cisplatin (10 mg/kg, IP) produces severe emesis in 4 out of 5 ferrets, pre-treatment with GIPR agonist GIP-523 (3 nmol/kg, SC) completely prevents cisplatin-induced vomiting (n = 5/group). C) GIPR agonism blocks the insurgence of cisplatin-induced emetic episodes (i.e. retching and vomiting) in ferrets (n = 5/group). D) Latency to the first emetic episode following each treatment condition in ferrets. E) In shrews, the profound emesis induced by cisplatin (30 mg/kg, IP) is significantly attenuated by GIP-085 (300 nmol/kg) pre-treatment (n = 8–16/group). F) Cumulative emetic episodes across time in shrews (n = 8–16/group). G) Latency to the first emetic episode following cisplatin treatment with or without GIPR agonist pre-treatment in shrews (n = 6–8/group). H) Cisplatin (6 mg/kg, IP) -induced anorexia is attenuated by GIPR agonism (GIP-085, 300 nmol/kg, IP) in rats (n = 12–15/group). I) Cisplatin leads to increased kaolin consumption (a proxy for nausea in rodents). GIPR agonism significantly attenuated cisplatin-induced kaolin consumption in rats (n = 12–15/group). J) Cisplatin-induced body weight loss is attenuated in rats pre-treated with GIP-085 (n = 12–15/group). K) Representative immunofluorescent images showing c-Fos-positive cells in the nucleus of the solitary tract (NTS) and area postrema (AP) (∼250 μm rostral to the obex) after GIP-085 (300 nmol/kg IP), cisplatin (6 mg/kg IP) or dual treatments. H) Quantification of c-Fos-positive neurons in the medial NTS and in the AP (n = 5/group). All data expressed as mean ± SEM. In the emetic studies, the number of animals vomiting and/or exhibiting retching, expressed as a fraction of the total number of animals tested are indicated above each treatment group. Data in (A, B, C, D, E, L) were analyzed with one-way ANOVA followed by Tukey's post hoc test. Data in (F, H, I, J) were analyzed with two-way ANOVA followed by Tukey's post hoc test. Means with different letters are significantly different from each other (P < 0.05). Data in (G) were analyzed with a two-tailed Student's t-test (∗P < 0.05).

Figure 2

Cisplatin primarily alters the transcriptome of GABA-ergic neurons and radial glia progenitor cells. A) A uniform manifold approximation and projection (UMAP) of AP/NTS identifying 20 cell types. B) Cellular subtypes were annotated with known markers of AP/NTS cellular subtypes. The size and color of dots are proportional to the percentage of cells expressing the gene (Pct. Exp.) and the average expression level of the gene (Avg. Exp.), respectively. The cluster numbers and colors are matched to that of the UMAP. Bar graphs represent the proportion of nuclei originating from each phenotype and were similar in all clusters. C) Volcano plots depicting the number of significant differential expression events induced by cisplatin and GDF15 treatment. D) The number of genes with cisplatin- or GDF15-altered expression per cluster. E) A highlighted UMAP showing the distribution of nuclei from the three phenotypes throughout all clusters. Cisplatin treatment induced a large enough alteration of the transcriptome in a population of GABA-ergic inhibitory neurons and radial glia progenitor cells to induce phenotype-specific partitioning of their UMAP, which coincided with these clusters having the largest number of differentially expressed genes. F) A highlighted UMAP identifying nuclei containing transcripts for Gipr.