Department of Medical Cell Biology, Gastrointestinal Physiology, Uppsala University, 751 23 Uppsala, Sweden.
Department of Pharmaceutical Biosciences, Translational Drug Discovery and Development, Uppsala University, 752 37 Uppsala, Sweden.
Int J Mol Sci. 2022 Mar 8;23(6):2912. doi: 10.3390/ijms23062912.
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 Cr-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.
疾病和/或化疗引起的肠道黏膜屏障功能障碍缺乏有效治疗方法，这凸显了强烈的医疗需求。我们的研究小组先前已经证明了褪黑素和米索前列醇在治疗由表面活性剂十二烷基硫酸钠（SDS）腔内暴露 15 分钟引起的肠道黏膜通透性增加方面的潜力。然而，尚不清楚腔内褪黑素和米索前列醇的有效浓度是多少，以及它们是否对较长时间的 SDS 暴露有效。本项在大鼠中进行的单次通过肠灌注研究的目的是调查褪黑素和米索前列醇对腔内 SDS 暴露 60 分钟引起的肠道通透性增加的浓度依赖性影响。通过评估腔内 SDS 引起的 Cr 标记 EDTA 的肠道清除率以及对暴露组织的组织学评估来研究细胞保护作用。10 和 100 µM 的褪黑素分别将 SDS 诱导的通透性增加降低了 50%。1 和 10 µM 的米索前列醇分别将通透性降低了 50%和 75%。两种药物在各自的最高浓度下联合使用没有附加的保护作用。这些体内结果支持进一步研究褪黑素和米索前列醇用于治疗功能失调的肠道屏障的口服治疗方法。
