Melatonin synergized with cyclosporine A improves cardiac allograft survival by suppressing inflammation and apoptosis

Abstract

Melatonin, a widespread physiological mediator, has been demonstrated to exhibit a dose‑dependent immunoregulatory effect in vitro and in vivo, including mediating physiological circadian rhythms, neutralizing free radicals and exerting antisenescence actions. In the present study, the efficacy and mechanism of melatonin alone or in combination with cyclosporine (CsA) in prolonging heart transplantation survival was examined. Daily treatment with melatonin (200 mg/kg/day) through a gavage, significantly prolonged the survival of cardiac grafts (mean survival time, 13.4±2.4 days; n=7; P<0.0001) compared with the untreated controls (5.8±1.2 days; n=7). When CsA (5 mg/kg/day) was co‑administered with melatonin (50 mg/kg/day), the survival rate improved (31.6±2.4 days; n=7; P<0.001), compared with that achieved by only 20 mg/kg/day CsA (22±2.8 days; n=7). As expected, melatonin significantly alleviated the inflammatory response and apoptosis as determined by TdT‑mediated dUTP‑biotin nick end labeling assay (P<0.05). Further analysis demonstrated that melatonin significantly reduced p65 activation and the release of inflammatory factors. Therefore, these findings indicate that melatonin in combination with CsA protected the cardiac allograft by inhibiting inflammation‑induced apoptosis. These results provide evidence for a novel therapeutic approach for future immunosuppressive agents in organ transplantation.

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