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Melatonin-Activated Receptor Signaling Pathways Mediate Protective Effects on Surfactant-Induced Increase in Jejunal
Karsten Peters1,2, David Dahlgren2, Hans Lennernäs2
1Department of Neuroscience, Gastrointestinal Physiology, Uppsala University, 751 24 Uppsala, Sweden.
Abstract:
A well-functional intestinal mucosal barrier can be compromised as a result of various diseases, chemotherapy, radiation, and chemical exposures including surfactants. Currently, there are no approved drugs targeting a dysfunctional intestinal barrier, which emphasizes a significant medical need. One candidate drug reported to regulate intestinal mucosal permeability is melatonin. However, it is still unclear if its effect is primarily receptor mediated or antioxidative, and if it is associated with enteric neural pathways. The aim of this rat intestinal perfusion study was to investigate the mechanisms of melatonin and nicotinic acetylcholine receptors on the increase in intestinal mucosal clearance of 51Cr-labeled ethylenediaminetetraacetate induced by 15 min luminal exposure to the anionic surfactant, sodium dodecyl sulfate. Our results show that melatonin abolished the surfactant-induced increase in intestinal permeability and that this effect was inhibited by luzindole, a melatonin receptor antagonist. In addition, mecamylamine, an antagonist of nicotinic acetylcholine receptors, reduced the surfactant-induced increase in mucosal permeability, using a signaling pathway not influenced by melatonin receptor activation. In conclusion, our results support melatonin as a potentially potent candidate for the oral treatment of a compromised intestinal mucosal barrier, and that its protective effect is primarily receptor-mediated.
Insights
Melatonin effectively protects the intestinal barrier from surfactant damage by acting through its receptors. This finding supports melatonin as a potential treatment for compromised intestinal permeability.
Area of Science:
- Gastroenterology
- Pharmacology
Background:
- The intestinal mucosal barrier is crucial for health but can be damaged by diseases, treatments, and chemicals.
- No current drugs specifically target a compromised intestinal barrier, highlighting a significant unmet medical need.
- Melatonin is a potential therapeutic agent for regulating intestinal permeability, but its precise mechanism of action remains unclear.
Purpose of the Study:
- To investigate the mechanisms by which melatonin and nicotinic acetylcholine receptors influence intestinal mucosal permeability.
- To determine if melatonin's protective effects on the intestinal barrier are receptor-mediated or antioxidative.
- To explore the involvement of enteric neural pathways in melatonin's action.
Main Methods:
- A rat intestinal perfusion model was used to assess intestinal mucosal clearance.
- The study exposed the intestine to sodium dodecyl sulfate (a surfactant) to induce increased permeability.
- The effects of melatonin, luzindole (melatonin receptor antagonist), and mecamylamine (nicotinic acetylcholine receptor antagonist) were evaluated.
Main Results:
- Melatonin administration abolished the increase in intestinal permeability induced by sodium dodecyl sulfate.
- The protective effect of melatonin was significantly inhibited by luzindole, indicating a receptor-mediated mechanism.
- Mecamylamine reduced surfactant-induced permeability via a pathway independent of melatonin receptor activation.
Conclusions:
- Melatonin demonstrates potent protective effects against surfactant-induced intestinal barrier dysfunction.
- Melatonin's therapeutic action on intestinal permeability is primarily mediated through its receptors.
- Melatonin is a promising candidate for oral treatment of compromised intestinal mucosal barrier conditions.
