Am J Perinatol 2017; 34(14): 1382-1388
DOI: 10.1055/s-0037-1604244
Review Article
Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Melatonin and Neonatal Sepsis: A Promising Antioxidant Adjuvant Agent

Gabriella D'Angelo
1   Department of Human Pathology in Adult and Developmental Age, University of Messina, Messina, Italy
Lucia Marseglia
1   Department of Human Pathology in Adult and Developmental Age, University of Messina, Messina, Italy
Russel J. Reiter
2   Department of Cellular and Structural Biology, University of Texas Health Science Center at San Antonio, San Antonio, Texas
Giuseppe Buonocore
3   Department of Molecular and Developmental Medicine, University of Siena, Siena, Italy
Eloisa Gitto
1   Department of Human Pathology in Adult and Developmental Age, University of Messina, Messina, Italy
› Author Affiliations
Further Information

Publication History

28 April 2017

08 June 2017

Publication Date:
13 July 2017 (online)


Sepsis represents a major clinical problem in neonatal setting with elevated mortality rate related to multiple organ failure. Despite decades of research, the exact mechanism of organ failure in sepsis is still not completely understood. Oxidative stress (OS), derived from an imbalance between pro-oxidant and antioxidant factors, is involved in the pathogenesis of several neonatal diseases, including sepsis, and plays a particular role in systemic organ failure. Recently, it has been recognized that administration of antioxidants could be useful in septic patients. Among all antioxidants, melatonin has a characteristic role as an antioxidant, anti-inflammatory, and anti-apoptotic agent. In combination with other interventions, melatonin may contribute to an improvement in septic organ injury. Furthermore, melatonin has already been widely used in treating various diseases of neonatal population, including asphyxia, respiratory distress, and sepsis, and no significant toxicity or treatment-related side effects with long-term melatonin therapy have been reported. This review aims to summarize current knowledge concerning the potential beneficial role of melatonin in septic neonates, supporting its short-term adjuvant co-therapy to reduce complications during neonatal sepsis.


As a review article, no research ethics application is required.



  • References

  • 1 Perez EM, Weisman LE. Novel approaches to the prevention and therapy of neonatal bacterial sepsis. Clin Perinatol 1997; 24 (01) 213-229
  • 2 Saugstad OD. Hypoxanthine as an indicator of hypoxia: its role in health and disease through free radical production. Pediatr Res 1988; 23 (02) 143-150
  • 3 Haynes RL, Folkerth RD, Keefe RJ. , et al. Nitrosative and oxidative injury to premyelinating oligodendrocytes in periventricular leukomalacia. J Neuropathol Exp Neurol 2003; 62 (05) 441-450
  • 4 Clyman RI, Saugstad OD, Mauray F. Reactive oxygen metabolites relax the lamb ductus arteriosus by stimulating prostaglandin production. Circ Res 1989; 64 (01) 1-8
  • 5 Bentlin MR, de Souza Rugolo LMS. Late-onset sepsis: epidemiology, evaluation, and outcome. Neoreviews 2010; 11 (08) e426-e435
  • 6 Lush CW, Kvietys PR. Microvascular dysfunction in sepsis. Microcirculation 2000; 7 (02) 83-101
  • 7 Abraham E, Singer M. Mechanisms of sepsis-induced organ dysfunction. Crit Care Med 2007; 35 (10) 2408-2416
  • 8 Wendel M, Heller AR. Mitochondrial function and dysfunction in sepsis. Wien Med Wochenschr 2010; 160 (5-6): 118-123
  • 9 Galley HF. Bench-to-bedside review: targeting antioxidants to mitochondria in sepsis. Crit Care 2010; 14 (04) 230
  • 10 Reiter RJ, Paredes SD, Manchester LC, Tan DX. Reducing oxidative/nitrosative stress: a newly-discovered genre for melatonin. Crit Rev Biochem Mol Biol 2009; 44 (04) 175-200
  • 11 Marseglia L, Aversa S, Barberi I. , et al. High endogenous melatonin levels in critically ill children: a pilot study. J Pediatr 2013; 162 (02) 357-360
  • 12 Gitto E, Marseglia L, Manti S. , et al. Protective role of melatonin in neonatal diseases. Oxid Med Cell Longev 2013; 2013: 980374
  • 13 Galano A, Tan DX, Reiter RJ. On the free radical scavenging activities of melatonin's metabolites, AFMK and AMK. J Pineal Res 2013; 54 (03) 245-257
  • 14 Venegas C, García JA, Escames G. , et al. Extrapineal melatonin: analysis of its subcellular distribution and daily fluctuations. J Pineal Res 2012; 52 (02) 217-227
  • 15 Víctor VM, Espulgues JV, Hernández-Mijares A, Rocha M. Oxidative stress and mitochondrial dysfunction in sepsis: a potential therapy with mitochondria-targeted antioxidants. Infect Disord Drug Targets 2009; 9 (04) 376-389
  • 16 Gitto E, Aversa S, Reiter RJ, Barberi I, Pellegrino S. Update on the use of melatonin in pediatrics. J Pineal Res 2011; 50 (01) 21-28
  • 17 Bersani I, Auriti C, Ronchetti MP, Prencipe G, Gazzolo D, Dotta A. Use of early biomarkers in neonatal brain damage and sepsis: state of the art and future perspectives. BioMed Res Int 2015; 2015: 253520
  • 18 Crouser ED. Mitochondrial dysfunction in septic shock and multiple organ dysfunction syndrome. Mitochondrion 2004; 4 (5-6): 729-741
  • 19 Rinaldi S, Landucci F, De Gaudio AR. Antioxidant therapy in critically septic patients. Curr Drug Targets 2009; 10 (09) 872-880
  • 20 Mishra UK, Jacobs SE, Doyle LW, Garland SM. Newer approaches to the diagnosis of early onset neonatal sepsis. Arch Dis Child Fetal Neonatal Ed 2006; 91 (03) F208-F212
  • 21 Berner R, Tüxen B, Clad A, Forster J, Brandis M. Elevated gene expression of interleukin-8 in cord blood is a sensitive marker for neonatal infection. Eur J Pediatr 2000; 159 (03) 205-210
  • 22 Schultz C, Temming P, Bucsky P, Göpel W, Strunk T, Härtel C. Immature anti-inflammatory response in neonates. Clin Exp Immunol 2004; 135 (01) 130-136
  • 23 Lowes DA, Webster NR, Murphy MP, Galley HF. Antioxidants that protect mitochondria reduce interleukin-6 and oxidative stress, improve mitochondrial function, and reduce biochemical markers of organ dysfunction in a rat model of acute sepsis. Br J Anaesth 2013; 110 (03) 472-480
  • 24 Galley HF. Oxidative stress and mitochondrial dysfunction in sepsis. Br J Anaesth 2011; 107 (01) 57-64
  • 25 Hirsiger S, Simmen HP, Werner CM, Wanner GA, Rittirsch D. Danger signals activating the immune response after trauma. Mediators Inflamm 2012; 2012: 315941
  • 26 Prauchner CA. Oxidative stress in sepsis: pathophysiological implications justifying antioxidant co-therapy. Burns 2017; 43 (03) 471-485
  • 27 von Dessauer B, Bongain J, Molina V, Quilodrán J, Castillo R, Rodrigo R. Oxidative stress as a novel target in pediatric sepsis management. J Crit Care 2011; 26 (01) 103.e1-103.e7
  • 28 Alonso de Vega JM, Díaz J, Serrano E, Carbonell LF. Oxidative stress in critically ill patients with systemic inflammatory response syndrome. Crit Care Med 2002; 30 (08) 1782-1786
  • 29 Goode HF, Cowley HC, Walker BE, Howdle PD, Webster NR. Decreased antioxidant status and increased lipid peroxidation in patients with septic shock and secondary organ dysfunction. Crit Care Med 1995; 23 (04) 646-651
  • 30 Parrillo JE, Burch C, Shelhamer JH, Parker MM, Natanson C, Schuette W. A circulating myocardial depressant substance in human with septic shock. Septic shock patients with a reduced ejection fraction have a circulating factor that depresses in vitro myocardial cell performance. J Clin Invest 1985; 76 (04) 1539-1553
  • 31 Parratt JR. Nitric oxide in sepsis and endotoxaemia. J Antimicrob Chemother 1998; 41 (Suppl A ): 31-39
  • 32 Kumar A, Brar R, Wang P. , et al. Role of nitric oxide and cGMP in human septic serum-induced depression of cardiac myocyte contractility. Am J Physiol 1999; 276 (1 Pt 2): R265-R276
  • 33 Brealey D, Brand M, Hargreaves I. , et al. Association between mitochondrial dysfunction and severity and outcome of septic shock. Lancet 2002; 360 (9328): 219-223
  • 34 Brown GC, Borutaite V. Nitric oxide and mitochondrial respiration in the heart. Cardiovasc Res 2007; 75 (02) 283-290
  • 35 Delanghe JR, Speeckaert MM. Translational research and biomarkers in neonatal sepsis. Clin Chim Acta 2015; 451 (Pt 0A): 46-64
  • 36 Sakr Y, Reinhart K, Bloos F. , et al. Time course and relationship between plasma selenium concentrations, systemic inflammatory response, sepsis, and multiorgan failure. Br J Anaesth 2007; 98 (06) 775-784
  • 37 Borrelli E, Roux-Lombard P, Grau GE. , et al. Plasma concentrations of cytokines, their soluble receptors, and antioxidant vitamins can predict the development of multiple organ failure in patients at risk. Crit Care Med 1996; 24 (03) 392-397
  • 38 Manzanares W, Dhaliwal R, Jiang X, Murch L, Heyland DK. Antioxidant micronutrients in the critically ill: a systematic review and meta-analysis. Crit Care 2012; 16 (02) R66
  • 39 Lerner AB, Case JD, Takahashi Y. Isolation of melatonin, a pineal factor that lightens melanocytes. J Am Chem Soc 1958; 80: 2587-2592
  • 40 Reiter RJ, Tan DX, Fuentes-Broto L. Melatonin: a multitasking molecule. Prog Brain Res 2010; 181: 127-151
  • 41 Gitto E, Pellegrino S, Gitto P, Barberi I, Reiter RJ. Oxidative stress of the newborn in the pre- and postnatal period and the clinical utility of melatonin. J Pineal Res 2009; 46 (02) 128-139
  • 42 Jan JE, Reiter RJ, Wasdell MB, Bax M. The role of the thalamus in sleep, pineal melatonin production, and circadian rhythm sleep disorders. J Pineal Res 2009; 46 (01) 1-7
  • 43 Pandi-Perumal SR, Trakht I, Spence DW, Srinivasan V, Dagan Y, Cardinali DP. The roles of melatonin and light in the pathophysiology and treatment of circadian rhythm sleep disorders. Nat Clin Pract Neurol 2008; 4 (08) 436-447
  • 44 Dauchy RT, Blask DE, Dauchy EM. , et al. Antineoplastic effects of melatonin on a rare malignancy of mesenchymal origin: melatonin receptor-mediated inhibition of signal transduction, linoleic acid metabolism and growth in tissue-isolated human leiomyosarcoma xenografts. J Pineal Res 2009; 47 (01) 32-42
  • 45 Gitto E, Marseglia L, D'Angelo G. , et al. Melatonin versus midazolam premedication in children undergoing surgery: A pilot study. J Paediatr Child Health 2016; 52 (03) 291-295
  • 46 Gitto E, Karbownik M, Reiter RJ. , et al. Effects of melatonin treatment in septic newborns. Pediatr Res 2001; 50 (06) 756-760
  • 47 Marseglia L, Cuppari C, Manti S. , et al. Atopic dermatitis: melatonin as potential treatment. J Biol Regul Homeost Agents 2015; 29 (2, Suppl 1) 142-149
  • 48 Li Volti G, Musumeci T, Pignatello R. , et al. Antioxidant potential of different melatonin-loaded nanomedicines in an experimental model of sepsis. Exp Biol Med (Maywood) 2012; 237 (06) 670-677
  • 49 Shang Y, Xu SP, Wu Y. , et al. Melatonin reduces acute lung injury in endotoxemic rats. Chin Med J (Engl) 2009; 122 (12) 1388-1393
  • 50 Wu JY, Tsou MY, Chen TH, Chen SJ, Tsao CM, Wu CC. Therapeutic effects of melatonin on peritonitis-induced septic shock with multiple organ dysfunction syndrome in rats. J Pineal Res 2008; 45 (01) 106-116
  • 51 Escames G, Acuña-Castroviejo D, López LC. , et al. Pharmacological utility of melatonin in the treatment of septic shock: experimental and clinical evidence. J Pharm Pharmacol 2006; 58 (09) 1153-1165
  • 52 Wu CC, Chiao CW, Hsiao G, Chen A, Yen MH. Melatonin prevents endotoxin-induced circulatory failure in rats. J Pineal Res 2001; 30 (03) 147-156
  • 53 Carrillo-Vico A, Lardone PJ, Naji L. , et al. Beneficial pleiotropic actions of melatonin in an experimental model of septic shock in mice: regulation of pro-/anti-inflammatory cytokine network, protection against oxidative damage and anti-apoptotic effects. J Pineal Res 2005; 39 (04) 400-408
  • 54 García JA, Ortiz F, Miana J. , et al. Contribution of inducible and neuronal nitric oxide synthases to mitochondrial damage and melatonin rescue in LPS-treated mice. J Physiol Biochem 2017; 73 (02) 235-244
  • 55 Sener G, Toklu H, Kapucu C. , et al. Melatonin protects against oxidative organ injury in a rat model of sepsis. Surg Today 2005; 35 (01) 52-59
  • 56 Ortiz F, García JA, Acuña-Castroviejo D. , et al. The beneficial effects of melatonin against heart mitochondrial impairment during sepsis: inhibition of iNOS and preservation of nNOS. J Pineal Res 2014; 56 (01) 71-81
  • 57 Fink T, Glas M, Wolf A. , et al. Melatonin receptors mediate improvements of survival in a model of polymicrobial sepsis. Crit Care Med 2014; 42 (01) e22-e31
  • 58 Doerrier C, García JA, Volt H. , et al. Permeabilized myocardial fibers as model to detect mitochondrial dysfunction during sepsis and melatonin effects without disruption of mitochondrial network. Mitochondrion 2016; 27: 56-63
  • 59 Srinivasan V, Pandi-Perumal SR, Spence DW, Kato H, Cardinali DP. Melatonin in septic shock: some recent concepts. J Crit Care 2010; 25 (04) 656.e1-656.e6
  • 60 Galano A, Tan DX, Reiter RJ. Melatonin as a natural ally against oxidative stress: a physicochemical examination. J Pineal Res 2011; 51 (01) 1-16
  • 61 Reiter RJ, Tan DX, Rosales-Corral S, Manchester LC. The universal nature, unequal distribution and antioxidant functions of melatonin and its derivatives. Mini Rev Med Chem 2013; 13 (03) 373-384
  • 62 Galley HF, Lowes DA, Allen L, Cameron G, Aucott LS, Webster NR. Melatonin as a potential therapy for sepsis: a phase I dose escalation study and an ex vivo whole blood model under conditions of sepsis. J Pineal Res 2014; 56 (04) 427-438
  • 63 Batra S, Kumar R, Kapoor AK, Ray G. Alterations in antioxidant status during neonatal sepsis. Ann Trop Paediatr 2000; 20 (01) 27-33
  • 64 Seema KR, Kumar R, Mandal RN. , et al. Serum TNF-alpha and free radical scavengers in neonatal septicemia. Indian J Pediatr 1999; 66 (04) 511-516
  • 65 Cancelier AC, Petronilho F, Reinke A. , et al. Inflammatory and oxidative parameters in cord blood as diagnostic of early-onset neonatal sepsis: a case-control study. Pediatr Crit Care Med 2009; 10 (04) 467-471
  • 66 Reiter RJ, Tan DX, Osuna C, Gitto E. Actions of melatonin in the reduction of oxidative stress. A review. J Biomed Sci 2000; 7 (06) 444-458
  • 67 Rodriguez C, Mayo JC, Sainz RM. , et al. Regulation of antioxidant enzymes: a significant role for melatonin. J Pineal Res 2004; 36 (01) 1-9
  • 68 El Frargy M, El-Sharkawy HM, Attia GF. Use of melatonin as an adjuvant therapy in neonatal sepsis. J Neonatal Perinatal Med 2015; 8 (03) 227-232
  • 69 El-Mashad AR, Elmahdy H, El-Dib M, Elbatch M, Aly H. Can melatonin be used as a marker for neonatal sepsis?. J Matern Fetal Neonatal Med 2016; 29 (17) 2870-2873
  • 70 Lowes DA, Almawash AM, Webster NR, Reid VL, Galley HF. Melatonin and structurally similar compounds have differing effects on inflammation and mitochondrial function in endothelial cells under conditions mimicking sepsis. Br J Anaesth 2011; 107 (02) 193-201
  • 71 López A, García JA, Escames G. , et al. Melatonin protects the mitochondria from oxidative damage reducing oxygen consumption, membrane potential, and superoxide anion production. J Pineal Res 2009; 46 (02) 188-198
  • 72 Volt H, García JA, Doerrier C. , et al. Same molecule but different expression: aging and sepsis trigger NLRP3 inflammasome activation, a target of melatonin. J Pineal Res 2016; 60 (02) 193-205
  • 73 Ortiz F, Acuña-Castroviejo D, Doerrier C. , et al. Melatonin blunts the mitochondrial/NLRP3 connection and protects against radiation-induced oral mucositis. J Pineal Res 2015; 58 (01) 34-49
  • 74 Lorente L, Martín MM, Abreu-González P. , et al. Serum melatonin levels are associated with mortality in severe septic patients. J Crit Care 2015; 30 (04) 860.e1-860.e6
  • 75 Bagci S, Horoz ÖÖ, Yildizdas D, Reinsberg J, Bartmann P, Müller A. Melatonin status in pediatric intensive care patients with sepsis. Pediatr Crit Care Med 2012; 13 (02) e120-e123
  • 76 Gitto E, Reiter RJ, Karbownik M. , et al. Causes of oxidative stress in the pre- and perinatal period. Biol Neonate 2002; 81 (03) 146-157
  • 77 Saugstad OD. Mechanisms of tissue injury by oxygen radicals: implications for neonatal disease. Acta Paediatr 1996; 85 (01) 1-4
  • 78 Shim H, Jang JY, Lee SH, Lee JG. Correlation of the oxygen radical activity and antioxidants and severity in critically ill surgical patients – study protocol. World J Emerg Surg 2013; 8 (01) 18
  • 79 Huet O, Dupic L, Harrois A, Duranteau J. Oxidative stress and endothelial dysfunction during sepsis. Front Biosci (Landmark Ed) 2011; 16: 1986-1995
  • 80 Martín M, Macías M, Escames G. , et al. Melatonin-induced increased activity of the respiratory chain complexes I and IV can prevent mitochondrial damage induced by ruthenium red in vivo. J Pineal Res 2000; 28 (04) 242-248
  • 81 Fulia F, Gitto E, Cuzzocrea S. , et al. Increased levels of malondialdehyde and nitrite/nitrate in the blood of asphyxiated newborns: reduction by melatonin. J Pineal Res 2001; 31 (04) 343-349
  • 82 Gitto E, Reiter RJ, Cordaro SP. , et al. Oxidative and inflammatory parameters in respiratory distress syndrome of preterm newborns: beneficial effects of melatonin. Am J Perinatol 2004; 21 (04) 209-216
  • 83 Gitto E, Reiter RJ, Amodio A. , et al. Early indicators of chronic lung disease in preterm infants with respiratory distress syndrome and their inhibition by melatonin. J Pineal Res 2004; 36 (04) 250-255
  • 84 Gitto E, Romeo C, Reiter RJ. , et al. Melatonin reduces oxidative stress in surgical neonates. J Pediatr Surg 2004; 39 (02) 184-189
  • 85 Jahnke G, Marr M, Myers C, Wilson R, Travlos G, Price C. Maternal and developmental toxicity evaluation of melatonin administered orally to pregnant Sprague-Dawley rats. Toxicol Sci 1999; 50 (02) 271-279
  • 86 Sánchez-Barceló EJ, Mediavilla MD, Tan DX, Reiter RJ. Clinical uses of melatonin: evaluation of human trials. Curr Med Chem 2010; 17 (19) 2070-2095
  • 87 Hu W, Deng C, Ma Z. , et al. Utilizing melatonin to combat bacterial infections and septic injury. Br J Pharmacol 2017; 174 (09) 754-768