D‐methionine improves cisplatin‐induced anorexia and dyspepsia syndrome by attenuating intestinal tryptophan hydroxylase 1 activity and increasing plasma leptin concentration

Abstract Background Cisplatin is a widely used antineoplastic drug. However, cisplatin‐induced dyspepsia syndromes, including delayed gastric emptying, gastric distension, early satiety, nausea, and vomiting, often force patients to take doses lower than those prescribed or even refuse treatment. D‐methionine has an appetite‐enhancing effect and alleviates weight loss during cisplatin treatment. Methods This work established a model of anorexia and dyspepsia symptoms with intraperitoneal injection of cisplatin (5 mg/kg) once a week for three cycles. Presupplementation with or without D‐methionine (300 mg/kg) was performed. Orexigenic and anorexigenic hormones (ghrelin, leptin, and glucagon‐like peptide‐1), tryptophan hydroxylase 1 (TPH1), 5‐hydroxytryptamine receptors (5‐HT 2C and 5‐HT 3 ), and hypothalamic feeding‐related peptides were measured by immunohistochemistry staining, enzyme‐linked immunosorbent assay, and real‐time PCR assay. Key results Cisplatin administration caused marked decrease in appetite and body weight, promoted adipose and fat tissue atrophy, and delayed gastric emptying and gastric distension, and D‐methionine preadministration prior to cisplatin administration significantly ameliorated these side effects. Besides, cisplatin induced an evident increase in serum ghrelin level, TPH1 activity, and 5‐HT 3 receptor expression in the intestine and decreased plasma leptin levels and gastric ghrelin mRNA gene expression levels. D‐methionine supplementation recovered these changes. The expression of orexigenic neuropeptide Y/agouti‐related peptide and anorexigenic cocaine‐ and amphetamine‐regulated transcript proopiomelanocortin neurons were altered by D‐methionine supplementation in cisplatin‐induced anorexia rats. Conclusions and inferences D‐methionine supplementation prevents cisplatin‐induced anorexia and dyspepsia syndrome possibly by attenuating intestinal tryptophan hydroxylase 1 activity and increasing plasma leptin concentration. Therefore, D‐methionine can be used as an adjuvant therapy for treating cisplatin‐induced adverse effects.