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

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 (200-250g) and male C3H/HeN wild-type and MT1/MT2 receptor knockout mice (20-22g). 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: 0.01/0.1/1.0/10mg/kg; mice: 1.0mg/kg), ramelteon, melatonin receptor-antagonist luzindole, ramelteon + luzindole, or melatonin + luzindole (each 1.0mg/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 [0.1mg/kg], 554min, [1.0mg/kg] 570min, [10mg/kg] 579min; sepsis/ramelteon, 468min; each p < 0.001 vs sepsis/vehicle, 303min) and wild-type mice (sepsis/melatonin, 781min; sepsis/ramelteon, 701min; both p < 0.001 vs sepsis/vehicle, 435min). 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-, 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.