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Melatonin Receptors Mediate Improvements of Survival in a Model of Polymicrobial Sepsis

Fink, Tobias MD1; Glas, Michael MD1; Wolf, Alexander MD1; Kleber, Astrid MD1; Reus, Erik MD1; Wolff, Martin MD1; Kiefer, Daniel MD1; Wolf, Beate1; Rensing, Hauke MD, PhD2; Volk, Thomas MD, PhD1; Mathes, Alexander M. MD, PhD, DESA, LLM3

doi: 10.1097/CCM.0b013e3182a63e2b
Online Laboratory Investigations

Objectives: Melatonin has been demonstrated to improve survival after experimental sepsis via antioxidant effects. Yet, recent evidence suggests that this protective capacity may also rely on melatonin receptor activation. Therefore, the present study was designed to investigate whether selective melatonin receptor-agonist ramelteon may influence survival and immune response in a model of polymicrobial sepsis in rats, wild-type and melatonin receptor MT1/MT2 double knockout mice.

Design: Prospective, randomized, controlled study.

Setting: University research laboratory.

Subjects: Male Sprague-Dawley rats (200–250 g) and male C3H/HeN wild-type and MT1/MT2 receptor knockout mice (20–22 g).

Interventions: Animals underwent cecal ligation and incision and remained anesthetized for evaluation of survival for 12 hours (rats: n = 15 per group) or 15 hours (mice: n = 10 per group). Analysis of immune response by means of enzyme-linked immunosorbent assay was performed before and 5 hours after cecal ligation and incision (rats only; n = 5 per group). After induction of sepsis, animals were treated IV with vehicle, different doses of melatonin (rats: 0.01/0.1/1.0/10 mg/kg; mice: 1.0 mg/kg), ramelteon, melatonin receptor-antagonist luzindole, ramelteon + luzindole, or melatonin + luzindole (each 1.0 mg/kg). Sham controls underwent laparotomy but not cecal ligation and incision.

Measurements and Main Results: Compared with vehicle, administration of ramelteon or melatonin significantly improved median survival time in rats (sepsis/melatonin [0.1 mg/kg], 554 min, [1.0 mg/kg] 570 min, [10 mg/kg] 579 min; sepsis/ramelteon, 468 min; each p < 0.001 vs sepsis/vehicle, 303 min) and wild-type mice (sepsis/melatonin, 781 min; sepsis/ramelteon, 701 min; both p < 0.001 vs sepsis/vehicle, 435 min). This effect was completely antagonized by coadministration of luzindole in all groups. Melatonin, ramelteon, or luzindole had no significant effect on survival time in knockout mice. Significantly elevated concentrations of tumor necrosis factor-α, interleukin-6, and interleukin-10 were observed 5 hours after cecal ligation and incision in rats (p < 0.05 vs baseline and corresponding sham); neither ramelteon nor melatonin treatment significantly affected immune response.

Conclusions: Melatonin receptors mediate improvements of survival after polymicrobial sepsis in rats and mice; this effect appears to be independent from major alterations of cytokine release.

1Department of Anaesthesiology, Intensive Care and Pain Therapy, Saarland University Medical Center, Homburg, Saarland, Germany.

2Department of Anaesthesiology and Critical Care Medicine, Leopoldina Hospital, Schweinfurt, Germany.

3Department of Anaesthesiology, Duesseldorf University Hospital, Duesseldorf, Germany.

This work was performed at Department of Anaesthesiology, Intensive Care and Pain Therapy, Saarland University Medical Center, Homburg, Saarland, Germany.

Supported, in part, by departmental funds.

Dr. Mathes received grant support from Else Kröner Fresenius Stiftung, Germany (Else Kröner Award 2011). The remaining authors have disclosed that they do not have any potential conflicts of interest.

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© 2014 by the Society of Critical Care Medicine and Lippincott Williams & Wilkins