Metabolomics approach to serum biomarker for loperamide-induced constipation in SD rats

Abstract

Loperamide has long been known as an opioid-receptor agonist useful as a drug for treatment of diarrhea resulting from gastroenteritis or inflammatory bowel disease as well as to induce constipation. To determine and characterize putative biomarkers that can predict constipation induced by loperamide treatment, alteration of endogenous metabolites was measured in the serum of Sprague Dawley (SD) rats treated with loperamide for 3 days using 1H nuclear magnetic resonance (1H NMR) spectral data. The amounts and weights of stool and urine excretion were significantly lower in the loperamide-treated group than the No-treated group, while the thickness of the villus, crypt layer, and muscle layer was decreased in the transverse colon of the same group. The concentrations of aspartate aminotransferase (AST), lactate dehydrogenase (LDH) and creatinine (Cr) were also slightly changed in the loperamide-treated group, although most of the serum components were maintained at a constant level. Furthermore, pattern recognition of endogenous metabolites showed completely separate clustering of the serum analysis parameters between the No-treated group and loperamide-treated group. Among 35 endogenous metabolites, four amino acids (alanine, glutamate, glutamine and glycine) and six endogenous metabolites (acetate, glucose, glycerol, lactate, succinate and taurine) were dramatically decreased in loperamide-treated SD rats. These results provide the first data pertaining to metabolic changes in SD rats with loperamide-induced constipation. Additionally, these findings correlate the changes in 10 metabolites with constipation.

Uridine stimulate laxative effect in the loperamide-induced constipation of SD rats through regulation of the mAChRs signaling pathway and mucin secretion

“…Alterations in endogenous metabolites were also examined in the serum of Lop-induced constipation rats. Among 35 endogenous metabolites, four amino acids (alanine, glutamate, glutamine and glycine) and six endogenous metabolites related to the glycolysis pathway (acetate, glucose, glycerol, lactate, succinate and taurine) were dramatically decreased after Lop treatment [ 52 ]. These results provide a possibility that Urd can rescue the Lop-induced constipation by interfering with the balance of metabolites because Urd plays a role in the glycolysis pathway of galactose [ 53 ].…”

Nuclear magnetic resonance‐ and mass spectrometry‐based metabolomics to study maleic acid toxicity from repeated dose exposure in rats

“…Some studies previously reported that inhibition of acetate and acetyl‐CoA carboxylase may lead to the accumulation of long‐chain acyl‐CoA, resulting in inadequate carbohydrate metabolism (Viola et al, ). Similarly, succinate is an intermediate in the TCA cycle and its decrease in concentration, though yet to reach statistical significance, also signals that TCA cycle is downregulated (Kim et al, ). We thus postulate the decrease of acetate in MA‐exposed rats can debilitate the TCA cycle, demonstrating MA exposure may disrupt energy production.…”

Laxative effects ofLiriope platyphyllaare tightly correlated with suppression of endoplasmic reticulum stress in loperamide-induced constipation of SD rats

“…Constipation is a chronic gastrointestinal disorder caused by various factors including insufficient dietary fiber intake, inadequate fluid intake, decreased physical activity, side effects of medication, hypothyroidism, and obstruction caused by colorectal cancer [ 19 ]. Recently, many studies have focused on investigation of the basic causes, development of novel therapeutic drugs and identification of molecular mechanisms responsible for constipation [ 20 21 23 ]. In an effort to investigate the molecular mechanisms associated with this disease, we investigated the role of Lop as an ER stressor, as well as the correlation between ER stress response and the laxative effect of L. platyphylla .…”