title: 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.
authors: Department of Cardiac Surgery, Zhongshan Hospital, Fudan University, Shanghai 200032, P.R. China.
authors: Chen
authors: C
authors: Liu
authors: Department of Cardiac Surgery, Zhongshan Hospital, Fudan University, Shanghai 200032, P.R. China.
authors: Tao
authors: T
authors: Hong
authors: Department of Cardiac Surgery, Zhongshan Hospital, Fudan University, Shanghai 200032, P.R. China.
authors: Mengping
authors: M
authors: Shao
authors: Department of Cardiac Surgery, Zhongshan Hospital, Fudan University, Shanghai 200032, P.R. China.
authors: Zhenghang
authors: Z
authors: Chen
authors: Department of Cardiac Surgery, Zhongshan Hospital, Fudan University, Shanghai 200032, P.R. China.
authors: Chunsheng
authors: C
authors: Wang
mesh_terms: D064591:Allografts; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D016572:Cyclosporine / Q000494:pharmacology*; D004357:Drug Synergism; D006085:Graft Survival / Q000187:drug effects; D006321:Heart / Q000187:drug effects / Q000502:physiology; D016027:Heart Transplantation; D007166:Immunosuppressive Agents / Q000494:pharmacology; D007249:Inflammation / Q000188:drug therapy / Q000517:prevention & control*; D053583:Interleukin-1beta / Q000235:genetics / Q000378:metabolism; D007376:Interleukin-2 / Q000097:blood; D008297:Male; D008550:Melatonin / Q000494:pharmacology*; D032342:Muscle Cells / Q000187:drug effects / Q000378:metabolism; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D029543:Nucleocytoplasmic Transport Proteins / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D014409:Tumor Necrosis Factor-alpha / Q000097:blood; D051028:bcl-2-Associated X Protein / Q000235:genetics / Q000378:metabolism
chemical_list: C494828:Bax protein, rat; D007166:Immunosuppressive Agents; D053583:Interleukin-1beta; D007376:Interleukin-2; D009363:Neoplasm Proteins; D029543:Nucleocytoplasmic Transport Proteins; D014409:Tumor Necrosis Factor-alpha; D051028:bcl-2-Associated X Protein; C063447:p65 oncofetal mRNA transport protein, rat; D016572:Cyclosporine; D008550:Melatonin