Prevention of Rat Intestinal Injury with a Drug Combination of Melatonin and Misoprostol

Abstract

A healthy intestinal barrier prevents uptake of allergens and toxins, whereas intestinal permeability increases following chemotherapy and in many gastrointestinal and systemic diseases and disorders. Currently, there are no approved drugs that target and repair the intestinal epithelial barrier while there is a medical need for such treatment in gastrointestinal and related conditions. The objective of this single-pass intestinal perfusion study in rats was to investigate the preventive cytoprotective effect of three mucosal protective drugs—melatonin, misoprostol, and teduglutide—with different mechanisms of action on an acute jejunal injury induced by exposing the intestine for 15 min to the anionic surfactant, sodium dodecyl sulfate (SDS). The effect was evaluated by monitoring intestinal clearance of 51Cr-labeled ethylenediaminetetraacetate and intestinal histology before, during, and after luminal exposure to SDS. Our results showed that separate pharmacological pretreatments with luminal misoprostol and melatonin reduced acute SDS-induced intestinal injury by 47% and 58%, respectively, while their use in combination abolished this injury. This data supports further development of drug combinations for oral treatments of conditions and disorders related to a dysregulated or compromised mucosal epithelial barrier.

Melatonin-Activated Receptor Signaling Pathways Mediate Protective Effects on Surfactant-Induced Increase in Jejunal Mucosal Permeability in Rats

“…It was clearly shown that melatonin attenuated the SDS-induced increase in jejunal mucosal permeability. This effect is previously reported [ 24 ], but it is unclear if it is mediated by melatonin receptors or by its antioxidative effects. To investigate the mechanisms we used luzindole, a potent melatonin receptor antagonist [ 36 ].…”

“…The primary scope of the present study was to elucidate the mechanisms of melatonin in response to an acute increase in jejunal mucosal permeability induced by 15 min SDS exposure of the jejunum in a rat single-pass intestinal perfusion (SPIP) model [ 19 , 24 ]. It was clearly shown that melatonin attenuated the SDS-induced increase in jejunal mucosal permeability.…”

“…SDS is an anionic surfactant commonly used as a pharmaceutical excipient in many oral dosage forms. At high amounts in the intestinal lumen, SDS has the potential to alter epithelial barrier integrity and it has been shown to increase permeability in both the absorptive and secretive directions [ 23 , 24 ]. However, it is currently unclear if the capacity of melatonin to inhibit the surfactant-induced increase in intestinal permeability is receptor mediated or antioxidative, which calls for further investigations of the mechanisms involved [ 24 ].…”

Chemotherapeutics-Induced Intestinal Mucositis: Pathophysiology and Potential Treatment Strategies

“…It should therefore be investigated for limiting CIM, in particular in synergism with other treatments. For example, melatonin dosed with misoprostol abolishes unselective surfactant-induced intestinal injury in rat ( Dahlgren et al, 2020 ).…”

“…Despite substantial improvements in cancer treatments and a continuous decline in its incidence in the population, CIM remains a significant and common clinical challenge in many cancer patients ( Henley et al, 2020 ). Consequently, there is a strong consensus that effective strategies are needed for the prevention and treatment of CIM, including new monotherapies and drug combinations ( Scarpignato and Bjarnason, 2019 ; Dahlgren et al, 2020 ). Crucial to this endeavor is a better understanding of the pathophysiological factors and adaptive processes involved in the regulation and repair of an injured intestinal epithelium ( Odenwald and Turner, 2017 ).…”