Gastric myoelectric activity during cisplatin-induced acute and delayed emesis reveals a temporal impairment of slow waves in ferrets: effects not reversed by the GLP-1 receptor antagonist, exendin (9-39)

// Zengbing Lu 1 , Man P. Ngan 1 , Ge Lin 1 , David T.W. Yew 1 , Xiaodan Fan 3 , Paul L.R. Andrews 4 and John A. Rudd 1, 2 1 School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China 2 Brain and Mind Institute, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, China 3 Department of Statistics, The Chinese University of Hong Kong, Hong Kong SAR, China 4 Division of Biomedical Sciences, St George’s University of London, London, UK Correspondence to: John A. Rudd, email: jar@cuhk.edu.hk Keywords: cisplatin; GLP-1 receptors; gastric myoelectric activity; ferret; emesis Received: May 19, 2017      Accepted: August 23, 2017      Published: October 16, 2017 ABSTRACT Preclinical studies show that the glucagon-like peptide-1 (GLP-1) receptor antagonist, exendin (9-39), can reduce acute emesis induced by cisplatin. In the present study, we investigate the effect of exendin (9-39) (100 nmol/24 h, i.c.v), on cisplatin (5 mg/kg, i.p.)-induced acute and delayed emesis and changes indicative of ‘nausea’ in ferrets. Cisplatin induced 37.2 ± 2.3 and 59.0 ± 7.7 retches + vomits during the 0-24 (acute) and 24-72 h (delayed) periods, respectively. Cisplatin also increased ( P <0.05) the dominant frequency of gastric myoelectric activity from 9.4 ± 0.1 to 10.4 ± 0.41 cpm and decreased the dominant power (DP) during acute emesis; there was a reduction in the % power of normogastria and an increase in the % power of tachygastria; food and water intake was reduced. DP decreased further during delayed emesis, where normogastria predominated. Advanced multifractal detrended fluctuation analysis revealed that the slow wave signal shape became more simplistic during delayed emesis. Cisplatin did not affect blood pressure (BP), but transiently increased heart rate, and decreased heart rate variability (HRV) during acute emesis; HRV spectral analysis indicated a shift to ‘sympathetic dominance’. A hyperthermic response was seen during acute emesis, but hypothermia occurred during delayed emesis and there was also a decrease in HR. Exendin (9-39) did not improve feeding and drinking but reduced cisplatin-induced acute emesis by ~59 % ( P <0.05) and antagonised the hypothermic response ( P <0.05); systolic, diastolic and mean arterial BP increased during the delayed phase. In conclusion, blocking GLP-1 receptors in the brain reduces cisplatin-induced acute but not delayed emesis. Restoring power and structure to slow waves may represent a novel approach to treat the side effects of chemotherapy.