Hindbrain GLP-1 receptor mediation of cisplatin-induced anorexia and nausea

Abstract

While chemotherapy-induced nausea and vomiting is clinically controlled in the acute (<24h) phase following treatment, the anorexia, nausea, fatigue, and other illness-type behaviors during the delayed phase (>24h) of chemotherapy are largely uncontrolled. As the hindbrain glucagon-like peptide-1 (GLP-1) system contributes to energy balance and mediates aversive and stressful stimuli, here we examine the hypothesis that hindbrain GLP-1 signaling mediates aspects of chemotherapy-induced nausea and reductions in feeding behavior in rats. Specifically, hindbrain GLP-1 receptor (GLP-1R) blockade, via 4th intracerebroventricular (ICV) exendin-(9-39) injections, attenuates the anorexia, body weight reduction, and pica (nausea-induced ingestion of kaolin clay) elicited by cisplatin chemotherapy during the delayed phase (48hr) of chemotherapy-induced nausea. Additionally, the present data provide evidence that the central GLP-1-producing preproglucagon neurons in the nucleus tractus solitarius (NTS) of the caudal brainstem are activated by cisplatin during the delayed phase of chemotherapy-induced nausea, as cisplatin led to a significant increase in c-Fos immunoreactivity in NTS GLP-1-immunoreactive neurons. These data support a growing body of literature suggesting that the central GLP-1 system may be a potential pharmaceutical target for adjunct anti-emetics used to treat the delayed-phase of nausea and emesis, anorexia, and body weight loss that accompany chemotherapy treatments.

A vitamin B12 conjugate of exendin‐4 improves glucose tolerance without associated nausea or hypophagia in rodents

“…40 The current data provide novel mechanistic evidence that B12 conjugation to a GLP-1R agonist can be used as a means to retain the hypoglycaemic properties of GLP-1R agonists while greatly reducing the CNS-mediated anorexia and illness effects observed with currently approved GLP-1-based ligands. 3,8,9 These studies are far from the complete set of in vivo glycaemic analyses needed for B12-Ex4, but certainly justify the need for more comprehensive future analyses. Further investigations are warranted to examine the acute actions of B12-Ex4 in diabetic animal models, as well as to evaluate the metabolic effects of chronic B12-Ex4 administration.…”

“…However, a sizeable percentage of individuals with T2DM does not have obesity or overweight and may want to avoid weight loss. Furthermore, it is important to note that the hypophagic effects of GLP‐1R agonists are accompanied by a pronounced incidence of nausea, vomiting and malaise . In fact, ~20% to 50% of T2DM patients receiving GLP‐1‐based medication experience nausea and/or vomiting, leading to discontinuation of drug treatment in ~6% to 10% and reduced dose tolerance in another ~15% .…”

“…This hyperglycaemic effect is unique to the Ex4 molecule (among approved GLP‐1R agonists) in the rat and is explained, in part, by CNS‐mediated sympathetic activation . Further, rats show well‐documented hypophagic effects to GLP‐1R ligands, mediated partly by accompanying acute effects on nausea/malaise, similar to humans, but not to mice . Rats were therefore used as the primary model to evaluate the effects of B12‐Ex4 on glycaemic control, energy balance and nausea/malaise, and these effects were compared with the response profile after peripheral administration of unconjugated Ex4.…”

“…Furthermore, it is important to note that the hypophagic effects of GLP-1R agonists are accompanied by a pronounced incidence of nausea, vomiting and malaise. 3,8,9 In fact, 20% to 50% of T2DM patients receiving GLP-1-based medication experience nausea and/or vomiting, leading to discontinuation of drug treatment in~6% to 10% and reduced dose tolerance in another 15%. [10][11][12][13][14] These adverse effects are surprisingly under-investigated, as they limit the widespread use, efficacy and potential ubiquitous utility of GLP-1R agonists (eg, liraglutide, exenatide) for the treatment of metabolic disease.…”

Leptin receptor–expressing nucleus tractus solitarius neurons suppress food intake independently of GLP1 in mice

“…GLP1 activity at sites within the CNS minimally alters food intake under normal conditions (11,(23)(24)(25)(26)(27)(28). Several food intake-suppressing stressors (including large volume loads in the stomach and chronic variable stress) activate GLP1 NTS cells, however, and interference with CNS GLP1 action or GLP1 NTS cells attenuates the acute anorexic response to these stressors (17,26). Thus, GLP1 NTS cells may modulate food intake mainly in response to particularly strong or stressful stimuli.…”