Melatonin Administration from 2000 to 2020 to Human Newborns with Hypoxic-Ischemic Encephalopathy

 

 Buy Article Permissions and Reprints

Abstract

Hypoxic-ischemic encephalopathy (HIE) is the main cause of long-term neurodevelopmental morbidity in term born infants worldwide. Melatonin is a hormone with antioxidant and anti-inflammatory effects that make it a promising molecule for the treatment of perinatal asphyxia. Probably, the synergistic use of hypothermia associated with melatonin treatment may improve the neurological outcome in infants with HIE. In the past 20 years, the efficacy of melatonin in reducing oxidative stress has been demonstrated in animals; however, clinical trials with sufficient sample size of newborns are lacking to date. Since in 2000 we were among the first to study the neuroprotective properties of melatonin on infants, in this review, we want to summarize the advantages and limitations of the investigations conducted to date.

Key Points

• HIE is the main cause of morbidity in term born infants worldwide.

• Melatonin is a promising molecule for the treatment of perinatal asphyxia.

• This review summarizes advantages and limitations of the investigations conducted on melatonin.

Authors' Contribution

G.D. conceptualized the study, L.C. designed and drafted the manuscript, R.J.R. acquired data, and E.G. critically revised the article for important intellectual content. All authors read and approved the final manuscript.

Publication History

Received: 26 March 2020

Accepted: 29 September 2020

Article published online:
31 October 2020

© 2020. Thieme. All rights reserved.

Thieme Medical Publishers, Inc.
333 Seventh Avenue, 18th Floor, New York, NY 10001, USA

• References

• 1 Kurinczuk JJ, White-Koning M, Badawi N. Epidemiology of neonatal encephalopathy and hypoxic-ischaemic encephalopathy. Early Hum Dev 2010; 86 (06) 329-338
  CrossrefPubMedGoogle Scholar
• 2 Tütüncüler F, Eskiocak S, Başaran UN, Ekuklu G, Ayvaz S, Vatansever U. The protective role of melatonin in experimental hypoxic brain damage. Pediatr Int 2005; 47 (04) 434-439
  CrossrefPubMedGoogle Scholar
• 3 McNally MA, Soul JS. Pharmacologic prevention and treatment of neonatal brain injury. Clin Perinatol 2019; 46 (02) 311-325
  CrossrefPubMedGoogle Scholar
• 4 Martinello K, Hart AR, Yap S, Mitra S, Robertson NJ. Management and investigation of neonatal encephalopathy: 2017 update. Arch Dis Child Fetal Neonatal Ed 2017; 102 (04) F346-F358
  CrossrefPubMedGoogle Scholar
• 5 Ibrani D, Molacavage S. The six-hour window: how the community hospital nursery can optimize outcomes of the infant with suspected hypoxic-ischemic encephalopathy. Neonatal Netw 2018; 37 (03) 155-163
  CrossrefPubMedGoogle Scholar
• 6 Millar LJ, Shi L, Hoerder-Suabedissen A, Molnár Z. Neonatal hypoxia ischaemia: mechanisms, models, and therapeutic challenges. Front Cell Neurosci 2017; 11: 78
  CrossrefPubMedGoogle Scholar
• 7 Fleiss B, Gressens P. Tertiary mechanisms of brain damage: a new hope for treatment of cerebral palsy?. Lancet Neurol 2012; 11 (06) 556-566
  CrossrefPubMedGoogle Scholar
• 8 Reiter RJ, Tan DX, Fuentes-Broto L. Melatonin: a multitasking molecule. Prog Brain Res 2010; 181: 127-151
  CrossrefPubMedGoogle Scholar
• 9 Brzezinski A. Melatonin in humans. N Engl J Med 1997; 336 (03) 186-195
  CrossrefPubMedGoogle Scholar
• 10 Marseglia L, D'Angelo G, Manti S. et al. Melatonin and atopy: role in atopic dermatitis and asthma. Int J Mol Sci 2014; 15 (08) 13482-13493
  CrossrefPubMedGoogle Scholar
• 11 Marseglia L, D'Angelo G, Manti S. et al. Analgesic, anxiolytic and anaesthetic effects of melatonin: new potential uses in pediatrics. Int J Mol Sci 2015; 16 (01) 1209-1220
  CrossrefPubMedGoogle Scholar
• 12 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
  CrossrefPubMedGoogle Scholar
• 13 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
  CrossrefPubMedGoogle Scholar
• 14 D'Angelo G, Marseglia L, Reiter RJ, Buonocore G, Gitto E. Melatonin and neonatal sepsis: a promising antioxidant adjuvant agent. Am J Perinatol 2017; 34 (14) 1382-1388
  Article in Thieme ConnectPubMedGoogle Scholar
• 15 Cardinali DP. An assessment of melatonin's therapeutic value in the hypoxic-ischemic encephalopathy of the newborn. Front Synaptic Neurosci 2019; 11: 34
  CrossrefPubMedGoogle Scholar
• 16 Ianăş O, Olinescu R, Bădescu I. Melatonin involvement in oxidative processes. Endocrinologie 1991; 29 (3-4): 147-153
  PubMedGoogle Scholar
• 17 Tan DX, Chen LD, Poeggeler B, Manchester LC, Reiter RJ. Melatonin: a potent, endogenous hydroxyl radical scavenger. Endocr J 1993; 1: 57-60
  PubMedGoogle Scholar
• 18 Miller SL, Yan EB, Castillo-Meléndez M, Jenkin G, Walker DW. Melatonin provides neuroprotection in the late-gestation fetal sheep brain in response to umbilical cord occlusion. Dev Neurosci 2005; 27 (2-4): 200-210
  CrossrefPubMedGoogle Scholar
• 19 Okatani Y, Wakatsuki A, Kaneda C. Melatonin increases activities of glutathione peroxidase and superoxide dismutase in fetal rat brain. J Pineal Res 2000; 28 (02) 89-96
  CrossrefPubMedGoogle Scholar
• 20 Kaur C, Sivakumar V, Ling EA. Melatonin protects periventricular white matter from damage due to hypoxia. J Pineal Res 2010; 48 (03) 185-193
  CrossrefPubMedGoogle Scholar
• 21 Thakor AS, Herrera EA, Serón-Ferré M, Giussani DA. Melatonin and vitamin C increase umbilical blood flow via nitric oxide-dependent mechanisms. J Pineal Res 2010; 49 (04) 399-406
  CrossrefPubMedGoogle Scholar
• 22 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
  CrossrefPubMedGoogle Scholar
• 23 Gitto E, Karbownik M, Reiter RJ. et al. Effects of melatonin treatment in septic newborns. Pediatr Res 2001; 50 (06) 756-760
  CrossrefPubMedGoogle Scholar
• 24 Gitto E, Marseglia L, Manti S. et al. Protective role of melatonin in neonatal diseases. Oxid Med Cell Longev 2013; 2013: 980374
  CrossrefPubMedGoogle Scholar
• 25 Gitto E, Reiter RJ, Sabatino G. et al. Correlation among cytokines, bronchopulmonary dysplasia and modality of ventilation in preterm newborns: improvement with melatonin treatment. J Pineal Res 2005; 39 (03) 287-293
  CrossrefPubMedGoogle Scholar
• 26 Gitto E, Aversa S, Salpietro CD. et al. Pain in neonatal intensive care: role of melatonin as an analgesic antioxidant. J Pineal Res 2012; 52 (03) 291-295
  CrossrefPubMedGoogle Scholar
• 27 Vitte PA, Harthe C, Lestage P, Claustrat B, Bobillier P. Plasma, cerebrospinal fluid, and brain distribution of 14C-melatonin in rat: a biochemical and autoradiographic study. J Pineal Res 1988; 5 (05) 437-453
  CrossrefPubMedGoogle Scholar
• 28 Menendez-Pelaez A, Reiter RJ. Distribution of melatonin in mammalian tissues: the relative importance of nuclear versus cytosolic localization. J Pineal Res 1993; 15 (02) 59-69
  CrossrefPubMedGoogle Scholar
• 29 Gupta YK, Gupta M, Kohli K. Neuroprotective role of melatonin in oxidative stress vulnerable brain. Indian J Physiol Pharmacol 2003; 47 (04) 373-386
  PubMedGoogle Scholar
• 30 Perrone S, Stazzoni G, Tataranno ML, Buonocore G. New pharmacologic and therapeutic approaches for hypoxic-ischemic encephalopathy in the newborn. J Matern Fetal Neonatal Med 2012; 25 (Suppl. 01) 83-88
  CrossrefPubMedGoogle Scholar
• 31 Cuzzocrea S, Costantino G, Gitto E. et al. Protective effects of melatonin in ischemic brain injury. J Pineal Res 2000; 29 (04) 217-227
  CrossrefPubMedGoogle Scholar
• 32 Welin AK, Svedin P, Lapatto R. et al. Melatonin reduces inflammation and cell death in white matter in the mid-gestation fetal sheep following umbilical cord occlusion. Pediatr Res 2007; 61 (02) 153-158
  CrossrefPubMedGoogle Scholar
• 33 Yawno T, Mahen M, Li J, Fahey MC, Jenkin G, Miller SL. The beneficial effects of melatonin administration following hypoxia-ischemia in preterm fetal sheep. Front Cell Neurosci 2017; 11: 296
  CrossrefPubMedGoogle Scholar
• 34 Bouslama M, Renaud J, Olivier P. et al. Melatonin prevents learning disorders in brain-lesioned newborn mice. Neuroscience 2007; 150 (03) 712-719
  CrossrefPubMedGoogle Scholar
• 35 Carloni S, Perrone S, Buonocore G, Longini M, Proietti F, Balduini W. Melatonin protects from the long-term consequences of a neonatal hypoxic-ischemic brain injury in rats. J Pineal Res 2008; 44 (02) 157-164
  PubMedGoogle Scholar
• 36 Olivier P, Fontaine RH, Loron G. et al. Melatonin promotes oligodendroglial maturation of injured white matter in neonatal rats. PLoS One 2009; 4 (09) e7128
  CrossrefPubMedGoogle Scholar
• 37 Lekic T, Manaenko A, Rolland W. et al. Neuroprotection by melatonin after germinal matrix hemorrhage in neonatal rats. Acta Neurochir Suppl (Wien) 2011; 111: 201-206
  CrossrefPubMedGoogle Scholar
• 38 Carloni S, Perrone S, Buonocore G, Longini M, Proietti F, Balduini W. Melatonin protects from the long-term consequences of a neonatal hypoxic-ischemic brain injury in rats. J Pineal Res 2008; 44 (02) 157-164
  CrossrefPubMedGoogle Scholar
• 39 Sivakumar V, Lu J, Ling EA, Kaur C. Vascular endothelial growth factor and nitric oxide production in response to hypoxia in the choroid plexus in neonatal brain. Brain Pathol 2008; 18 (01) 71-85
  CrossrefPubMedGoogle Scholar
• 40 Alonso-Alconada D, Alvarez A, Lacalle J, Hilario E. Histological study of the protective effect of melatonin on neural cells after neonatal hypoxia-ischemia. Histol Histopathol 2012; 27 (06) 771-783
  PubMedGoogle Scholar
• 41 Balduini W, Carloni S, Perrone S. et al. The use of melatonin in hypoxic-ischemic brain damage: an experimental study. J Matern Fetal Neonatal Med 2012; 25 (Suppl. 01) 119-124
  CrossrefPubMedGoogle Scholar
• 42 Carloni S, Facchinetti F, Pelizzi N, Buonocore G, Balduini W. Melatonin acts in synergy with hypothermia to reduce oxygen-glucose deprivation-induced cell death in rat hippocampus organotypic slice cultures. Neonatology 2018; 114 (04) 364-371
  CrossrefPubMedGoogle Scholar
• 43 Hu Y, Wang Z, Liu Y. et al. Melatonin reduces hypoxic-ischaemic (HI) induced autophagy and apoptosis: an in vivo and in vitro investigation in experimental models of neonatal HI brain injury. Neurosci Lett 2017; 653: 105-112
  CrossrefPubMedGoogle Scholar
• 44 Aridas JDS, Yawno T, Sutherland AE. et al. Systemic and transdermal melatonin administration prevents neuropathology in response to perinatal asphyxia in newborn lambs. J Pineal Res 2018; 64 (04) e12479
  CrossrefPubMedGoogle Scholar
• 45 Merchant N, Azzopardi D, Counsell S. et al. O-057 melatonin as a novel neuroprotectant in preterm infants − a double blinded randomised controlled trial (mint study). Arch Dis Child 2014; 99: A43
  CrossrefPubMedGoogle Scholar
• 46 Paprocka J, Kijonka M, Rzepka B, Sokół M. Melatonin in hypoxic-ischemic brain injury in term and preterm babies. Int J Endocrinol 2019; 2019: 9626715
  CrossrefPubMedGoogle Scholar
• 47 Gunn AJ, Gluckman PD, Gunn TR. Selective head cooling in newborn infants after perinatal asphyxia: a safety study. Pediatrics 1998; 102 (4 Pt 1): 885-892
  CrossrefPubMedGoogle Scholar
• 48 Jacobs SE, Morley CJ, Inder TE. et al; Infant Cooling Evaluation Collaboration. Whole-body hypothermia for term and near-term newborns with hypoxic-ischemic encephalopathy: a randomized controlled trial. Arch Pediatr Adolesc Med 2011; 165 (08) 692-700
  CrossrefPubMedGoogle Scholar
• 49 Jacobs SE, Berg M, Hunt R, Tarnow-Mordi WO, Inder TE, Davis PG. Cooling for newborns with hypoxic ischaemic encephalopathy. Cochrane Database Syst Rev 2013; 31 (01) CD003311
  PubMedGoogle Scholar
• 50 Lee CYZ, Chakranon P, Lee SWH. Comparative efficacy and safety of neuroprotective therapies for neonates with hypoxic ischemic encephalopathy: a network meta-analysis. Front Pharmacol 2019; 10: 1221
  CrossrefPubMedGoogle Scholar
• 51 Robertson NJ, Faulkner S, Fleiss B. et al. Melatonin augments hypothermic neuroprotection in a perinatal asphyxia model. Brain 2013; 136 (Pt 1): 90-105
  CrossrefPubMedGoogle Scholar
• 52 Aly H, Elmahdy H, El-Dib M. et al. Melatonin use for neuroprotection in perinatal asphyxia: a randomized controlled pilot study. J Perinatol 2015; 35 (03) 186-191
  CrossrefPubMedGoogle Scholar
• 53 Ahmad QM, Chishti AL, Waseem N. Role of melatonin in management of hypoxic ischaemic encephalopathy in newborns: a randomized control trial. J Pak Med Assoc 2018; 68 (08) 1233-1237
  PubMedGoogle Scholar
• 54 Merchant NM, Azzopardi DV, Hawwa AF. et al. Pharmacokinetics of melatonin in preterm infants. Br J Clin Pharmacol 2013; 76 (05) 725-733
  CrossrefPubMedGoogle Scholar
• 55 Robertson NJ, Martinello K, Lingam I. et al. Melatonin as an adjunct to therapeutic hypothermia in a piglet model of neonatal encephalopathy: a translational study. Neurobiol Dis 2019; 121: 240-251
  CrossrefPubMedGoogle Scholar
• 56 Carloni S, Proietti F, Rocchi M. et al. Melatonin pharmacokinetics following oral administration in preterm neonates. Molecules 2017; 22 (12) 2115-2017
  CrossrefPubMedGoogle Scholar
• 57 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
  CrossrefPubMedGoogle Scholar
• 58 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
  Article in Thieme ConnectPubMedGoogle Scholar
• 59 Balduini W, Weiss MD, Carloni S. et al. Melatonin pharmacokinetics and dose extrapolation after enteral infusion in neonates subjected to hypothermia. J Pineal Res 2019; 66 (04) e12565
  CrossrefPubMedGoogle Scholar
• 60 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
  CrossrefPubMedGoogle Scholar