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

Neurogastroenterol Motil. 2020 Jun;32(6):e13803. doi: 10.1111/nmo.13803. Epub 2020 Jan 27.

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-HT2C and 5-HT3 ), 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-HT3 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.

Keywords: 5-HT3 receptor; D-methionine; anorexia; cisplatin; dyspepsia syndrome.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anorexia / chemically induced*
  • Antineoplastic Agents / administration & dosage*
  • Cisplatin / administration & dosage*
  • Dyspepsia / chemically induced*
  • Ghrelin / blood
  • Hypothalamus / drug effects
  • Hypothalamus / metabolism
  • Intestinal Mucosa / drug effects*
  • Intestinal Mucosa / metabolism
  • Leptin / blood*
  • Male
  • Methionine / administration & dosage*
  • Rats, Wistar
  • Receptors, Serotonin, 5-HT3 / metabolism
  • Tryptophan Hydroxylase / metabolism*

Substances

  • Antineoplastic Agents
  • Ghrelin
  • Leptin
  • Receptors, Serotonin, 5-HT3
  • Methionine
  • Tph1 protein, mouse
  • Tryptophan Hydroxylase
  • Cisplatin

Associated data

  • GENBANK/NM_031144.3
  • GENBANK/NM_021669.2
  • GENBANK/NM_012614.2
  • GENBANK/NM_033650.1
  • GENBANK/NM_139326.2
  • GENBANK/NM_017110.1
  • GENBANK/NM_012765.3