Melatonin and structurally similar compounds have differing effects on inflammation and mitochondrial function in endothelial cells under conditions mimicking sepsis

• Published in: British journal of anaesthesia : BJA Vol. 107; no. 2; pp. 193 - 201
• Main Authors: Lowes, D.A., Almawash, A.M., Webster, N.R., Reid, V.L., Galley, H.F.
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Ltd 01.08.2011; Oxford University Press
• Subjects: Anesthesia; Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy; Antioxidants - pharmacology; Biological and medical sciences; Cells, Cultured; Endothelium, Vascular - cytology; Endothelium, Vascular - drug effects; glutathione; Glutathione - metabolism; Humans; indoleamines; Inflammation - metabolism; Inflammation - pathology; Inflammation - physiopathology; Interleukin-6 - metabolism; Interleukin-8 - metabolism; Medical sciences; melatonin; Melatonin - pharmacology; Membrane Potential, Mitochondrial - drug effects; Membrane Potential, Mitochondrial - physiology; mitochondria; Mitochondria - drug effects; NF-kappa B - metabolism; oxidative stress; Oxidative Stress - drug effects; Oxidative Stress - physiology; sepsis; Sepsis - metabolism; Sepsis - pathology; Sepsis - physiopathology; Signal Transduction - drug effects; Signal Transduction - physiology; tryptamine; tryptamine; indoleamines; glutathione; mitochondria; melatonin; oxidative stress; sepsis; Oxidative stress; Endothelial cell; Melatonin; Tryptamine; Inflammation; Differential diagnostic; Infection; Sepsis syndrome; Mitochondria; Anesthesia; Pineal hormone; Glutathione
• ISSN: 0007-0912; 1471-6771
• DOI: 10.1093/bja/aer149

Development of organ dysfunction associated with sepsis is due in part to oxidative damage to mitochondria. Melatonin regulates the sleep–wake cycle and also has potent antioxidant activity. The aim of this study was to determine the effects of melatonin and other structurally related compounds on mitochondrial function, endogenous glutathione (GSH), and control of cytokine expression under conditions mimicking sepsis. Human endothelial cells were treated with lipopolysaccharide (LPS) plus peptidoglycan G (PepG) to simulate sepsis, in the presence of melatonin, 6-hydroxymelatonin, tryptamine, or indole-3-carboxylic acid. Nuclear factor κB (NFκB) activation, interleukin (IL)-6 and IL-8, total glutathione, mitochondrial membrane potential, and metabolic activity were measured. LPS and PepG treatment resulted in elevated IL-6 and IL-8 levels preceded by activation of NFκB (all P<0.0001). Treatment with all four compounds resulted in lower IL-6 and IL-8 levels, and lower NFκB activation (P<0.0001). Loss of mitochondrial membrane potential and endogenous glutathione was seen when cells were exposed to LPS/PepG, but these were maintained in cells co-treated with melatonin, tryptamine, or 6-hydroxymelatonin (P<0.05), but not indole-3-carboxylic acid. Metabolic activity decreased after exposure to LPS/PepG and was maintained by melatonin and 6-hydroxymelatonin at the highest concentrations only. We have shown that in addition to melatonin, other structurally related indoleamine compounds have effects on NFκB activation and cytokine expression, GSH, mitochondrial membrane potential, and metabolic activity in endothelial cells cultured under conditions mimicking sepsis. Further work is needed to determine whether these compounds represent therapeutic approaches for disrupting the oxidative stress-inflammatory response signalling pathway in sepsis.