title: Circadian variation in the response to experimental endotoxemia and modulatory effects of exogenous melatonin.
abstract: Disturbances in circadian rhythms are commonly observed in the development of several medical conditions and may also be involved in the pathophysiology of sepsis. Melatonin, with its antioxidative and anti-inflammatory effects, is known to modulate the response to endotoxemia. In this paper, we investigated the circadian variation with or without melatonin administration in an experimental endotoxemia model based on lipopolysaccharide (LPS). Sixty male Sprague-Dawley rats were assigned to six groups receiving an intraperitoneal injection of either LPS (5 mg/kg), LPS + melatonin (1 mg/kg), or LPS + melatonin (10 mg/kg) at either daytime or nighttime. Superoxide dismutase (SOD) was analyzed in liver samples collected after decapitation. Furthermore, inflammatory plasma markers (cytokines interleukin [IL]-6, IL-10) and oxidative plasma markers (ascorbic acid [AA], dehydroascorbic acid [DHA], and malondialdehyde [MDA]) were analyzed before and 5 h after the onset of endotoxemia. There were significant higher levels of SOD (p < 0.05), IL-6 (p < 0.01), and IL-10 (p < 0.05) during nighttime endotoxemia compared with daytime. At daytime, melatonin 1 and 10 mg reduced the levels of MDA and increased SOD, IL-6, IL-10, and DHA (p < 0.05). At nighttime, melatonin reduced the levels of MDA and increased DHA (p < 0.05). Additionally, 10 mg melatonin resulted in lower levels of AA during daytime (p < 0.05). No dose relationship of melatonin was observed. The results showed that the response induced by experimental endotoxemia was dependent on time of day. Melatonin administration modulated the inflammatory and oxidative stress responses induced by endotoxemia and also resulted in higher levels of antioxidants during daytime. The effect of circadian time on the endotoxemia response and possible modulatory effects of melatonin need further investigations in a human endotoxemia model.
authors.affiliation: Department of Surgical Gastroenterology, University of Copenhagen, Herlev Hospital , Copenhagen , Denmark and.
authors.forename: Mahdi
authors.initials: M
authors.lastname: Alamili
authors.forename: Mads
authors.initials: M
authors.lastname: Klein
authors.forename: Jens
authors.initials: J
authors.lastname: Lykkesfeldt
authors.forename: Jacob
authors.initials: J
authors.lastname: Rosenberg
authors.forename: Ismail
authors.initials: I
authors.lastname: Gögenur
mesh_terms: D000210:Acute-Phase Reaction; D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D001205:Ascorbic Acid / Q000378:metabolism; D002940:Circadian Rhythm; D003624:Darkness; D004195:Disease Models, Animal; D019446:Endotoxemia / Q000097:blood* / Q000276:immunology; D007249:Inflammation; D016753:Interleukin-10 / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D008027:Light; D008070:Lipopolysaccharides / Q000378:metabolism; D008297:Male; D008315:Malondialdehyde / Q000378:metabolism; D008550:Melatonin / Q000378:metabolism*; D018384:Oxidative Stress; D010100:Oxygen / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013482:Superoxide Dismutase / Q000378:metabolism
chemical_list: D000975:Antioxidants; D015850:Interleukin-6; D008070:Lipopolysaccharides; D016753:Interleukin-10; D008315:Malondialdehyde; D013482:Superoxide Dismutase; D008550:Melatonin; D001205:Ascorbic Acid; D010100:Oxygen