Protective Effects of Melatonin and Misoprostol against Experimentally Induced Increases in Intestinal Permeability in Rats.

Karsten Peters,David Dahlgren,Péter Pál Egerszegi,Hans Lennernäs,Markus Sjöblom

doi:10.3390/ijms23062912

Karsten Peters, David Dahlgren + Show 3 more

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https://doi.org/10.3390/ijms23062912

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Abstract

Intestinal mucosal barrier dysfunction caused by disease and/or chemotherapy lacks an effective treatment, which highlights a strong medical need. Our group has previously demonstrated the potential of melatonin and misoprostol to treat increases in intestinal mucosal permeability induced by 15-min luminal exposure to a surfactant, sodium dodecyl sulfate (SDS). However, it is not known which luminal melatonin and misoprostol concentrations are effective, and whether they are effective for a longer SDS exposure time. The objective of this single-pass intestinal perfusion study in rats was to investigate the concentration-dependent effect of melatonin and misoprostol on an increase in intestinal permeability induced by 60-min luminal SDS exposure. The cytoprotective effect was investigated by evaluating the intestinal clearance of 51Cr-labeled EDTA in response to luminal SDS as well as a histological evaluation of the exposed tissue. Melatonin at both 10 and 100 µM reduced SDS-induced increase in permeability by 50%. Misoprostol at 1 and 10 µM reduced the permeability by 50 and 75%, respectively. Combination of the two drugs at their respective highest concentrations had no additive protective effect. These in vivo results support further investigations of melatonin and misoprostol for oral treatments of a dysfunctional intestinal barrier.

Highlights

A healthy intestinal mucosa is a selective and dynamic barrier that separates the luminal contents from the systemic circulation [1]
In the control group (i.e., animals perfused luminally with an isotonic (290 mOsm) phosphate-buffered solution), jejunal epithelial permeability of 51 Cr-labeled ethylenediaminetetraacetate (51 Cr-EDTA) was stable and low (0.08–0.16 mL/min/100 g) throughout the 165-min experiment. This resulted in a total CLCr-EDTA
When sodium dodecyl sulfate (SDS) was withdrawn at t = 105 min, the increase in CLCr-EDTA ceased and stayed at a plateau for 30 min

Summary

Introduction

A healthy intestinal mucosa is a selective and dynamic barrier that separates the luminal contents from the systemic circulation [1]. The most prevalent subgroup of cells in the intestinal epithelium are enterocytes, making up about 94% of the jejunal cell population [2] They are shed and completely replaced every three to five days without any loss of barrier function [3]. Tight junction proteins at the luminal side of the epithelium regulate paracellular flux of hydrophilic molecules and electrolytes with low cell membrane permeability, in order to maintain intestinal and systemic homeostasis [4]. This is achieved through constant adaptation following hormonal, neural, and luminal stimuli, facilitated by the tight junction protein links to the intracellular actin cytoskeleton [5,6]

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