Efficacy of Melatonin in Term Neonatal Models of Perinatal Hypoxia-ischaemia

Overview

Journal Ann Clin Transl Neurol

Specialty Neurology

Date 2022 Apr 12

PMID 35413154

Authors

Raymand Pang

Hyun Jee Han

Christopher Meehan

Xavier Golay

Suzanne L Miller

Nicola J Robertson

Affiliations

Soon will be listed here.

Abstract

Objective: Neonatal encephalopathy (NE) is an important cause of mortality and disability worldwide. Therapeutic hypothermia (HT) is an effective therapy, however not all babies benefit. Novel agents are urgently needed to improve outcomes. Melatonin in preclinical studies has promising neuroprotective properties. This meta-analysis assessed the efficacy of melatonin in term animal models of NE on cerebral infarct size, neurobehavioural tests and cell death.

Methods: A literature search was carried out using Embase, MEDLINE and Web of Science (31 May 2021). We identified 14 studies and performed a meta-analysis with a random effects model using standardised mean difference (SMD) as the effect size. The risk of bias was assessed using the Systematic Review Centre for Laboratory animal Experimentation tool and publication bias was assessed with funnel plots, and adjusted using trim and fill analysis. Subgroup and meta-regression analyses were performed to assess the effects of study design variables.

Results: We observed significant reduction in brain infarct size (SMD -2.05, 95% CI [-2.93, -1.16]), improved neurobehavioural outcomes (SMD -0.86, 95% CI [-1.23, -0.53]) and reduction in cell death (SMD -0.60, 95% CI [-1.06, -0.14]) favouring treatment with melatonin. Neuroprotection was evident as a single therapy and combined with HT. Subgroup analysis showed greater efficacy with melatonin given before or immediately after injury and with ethanol excipients. The overall effect size remained robust even after adjustment for publication bias.

Interpretation: These studies demonstrate a significant neuroprotective efficacy of melatonin in term neonatal models of hypoxia-ischaemia, and suggest melatonin is a strong candidate for translation to clinical trials in babies with moderate-severe NE.

Citing Articles

Melatonin: a positive influencer of inflammation in neonatal encephalopathy.

Pang R, Molloy E, Robertson N Pediatr Res. 2025; .

PMID: 39833346 DOI: 10.1038/s41390-025-03876-7.

Neuroprotective Effect of Melatonin in a Neonatal Hypoxia-Ischemia Rat Model Is Regulated by the AMPK/mTOR Pathway.

Nacarkucuk E, Bernis M, Bremer A, Grzelak K, Zweyer M, Maes E J Am Heart Assoc. 2024; 13(19):e036054.

PMID: 39319465 PMC: 11681444. DOI: 10.1161/JAHA.124.036054.

Hypoxic-Ischemic Encephalopathy: Pathogenesis and Promising Therapies.

Yang M, Wang K, Liu B, Shen Y, Liu G Mol Neurobiol. 2024; 62(2):2105-2122.

PMID: 39073530 DOI: 10.1007/s12035-024-04398-9.

Neuroprotective effects of maternal melatonin administration in early-onset placental insufficiency and fetal growth restriction.

Malhotra A, Rocha A, Yawno T, Sutherland A, Allison B, Nitsos I Pediatr Res. 2024; 95(6):1510-1518.

PMID: 38225450 PMC: 11126390. DOI: 10.1038/s41390-024-03027-4.

[Research research on the use of melatonin in combination with therapeutic hypothermia for the treatment of neonatal hypoxic-ischemic encephalopathy].

Liu Y, Xia S Zhongguo Dang Dai Er Ke Za Zhi. 2023; 25(8):864-869.

PMID: 37668036 PMC: 10484075. DOI: 10.7499/j.issn.1008-8830.2302099.

References

Eklind S, Mallard C, Arvidsson P, Hagberg H . Lipopolysaccharide induces both a primary and a secondary phase of sensitization in the developing rat brain. Pediatr Res. 2005; 58(1):112-6. DOI: 10.1203/01.PDR.0000163513.03619.8D. View

Pang R, Avdic-Belltheus A, Meehan C, Martinello K, Mutshiya T, Yang Q . Melatonin and/or erythropoietin combined with hypothermia in a piglet model of perinatal asphyxia. Brain Commun. 2021; 3(1):fcaa211. PMC: 7876304. DOI: 10.1093/braincomms/fcaa211. View

Kochanski R, Peng C, Higashida T, Geng X, Huttemann M, Guthikonda M . Neuroprotection conferred by post-ischemia ethanol therapy in experimental stroke: an inhibitory effect on hyperglycolysis and NADPH oxidase activation. J Neurochem. 2013; 126(1):113-21. DOI: 10.1111/jnc.12169. View

Martinello K, Meehan C, Avdic-Belltheus A, Lingam I, Ragab S, Hristova M . Acute LPS sensitization and continuous infusion exacerbates hypoxic brain injury in a piglet model of neonatal encephalopathy. Sci Rep. 2019; 9(1):10184. PMC: 6629658. DOI: 10.1038/s41598-019-46488-y. View

Ozyener F, Cetinkaya M, Alkan T, Goren B, Kafa I, Kurt M . Neuroprotective effects of melatonin administered alone or in combination with topiramate in neonatal hypoxic-ischemic rat model. Restor Neurol Neurosci. 2012; 30(5):435-44. DOI: 10.3233/RNN-2012-120217. View

Revuelta M, Arteaga O, Alvarez A, Martinez-Ibarguen A, Hilario E . Characterization of Gene Expression in the Rat Brainstem After Neonatal Hypoxic-Ischemic Injury and Antioxidant Treatment. Mol Neurobiol. 2016; 54(2):1129-1143. DOI: 10.1007/s12035-016-9724-6. View

Vesterinen H, Sena E, Egan K, Hirst T, Churolov L, Currie G . Meta-analysis of data from animal studies: a practical guide. J Neurosci Methods. 2013; 221:92-102. DOI: 10.1016/j.jneumeth.2013.09.010. View

Mitra S, Kendall G, Bainbridge A, Sokolska M, Dinan M, Uria-Avellanal C . Proton magnetic resonance spectroscopy lactate/N-acetylaspartate within 2 weeks of birth accurately predicts 2-year motor, cognitive and language outcomes in neonatal encephalopathy after therapeutic hypothermia. Arch Dis Child Fetal Neonatal Ed. 2018; 104(4):F424-F432. DOI: 10.1136/archdischild-2018-315478. View

Robertson N, Martinello K, Lingam I, Avdic-Belltheus A, Meehan C, Alonso-Alconada D . Melatonin as an adjunct to therapeutic hypothermia in a piglet model of neonatal encephalopathy: A translational study. Neurobiol Dis. 2018; 121:240-251. DOI: 10.1016/j.nbd.2018.10.004. View

10.

Tann C, Nakakeeto M, Willey B, Sewegaba M, Webb E, Oke I . Perinatal risk factors for neonatal encephalopathy: an unmatched case-control study. Arch Dis Child Fetal Neonatal Ed. 2017; 103(3):F250-F256. PMC: 5916101. DOI: 10.1136/archdischild-2017-312744. View

11.

DAngelo G, Cannavo L, Reiter R, Gitto E . Melatonin Administration from 2000 to 2020 to Human Newborns with Hypoxic-Ischemic Encephalopathy. Am J Perinatol. 2020; 39(8):824-829. DOI: 10.1055/s-0040-1719151. View

12.

Robertson N, Faulkner S, Fleiss B, Bainbridge A, Andorka C, Price D . Melatonin augments hypothermic neuroprotection in a perinatal asphyxia model. Brain. 2012; 136(Pt 1):90-105. DOI: 10.1093/brain/aws285. View

13.

Carloni S, Proietti F, Rocchi M, Longini M, Marseglia L, DAngelo G . Melatonin Pharmacokinetics Following Oral Administration in Preterm Neonates. Molecules. 2017; 22(12). PMC: 6149762. DOI: 10.3390/molecules22122115. View

14.

Jacobs S, Berg M, Hunt R, Tarnow-Mordi W, Inder T, Davis P . Cooling for newborns with hypoxic ischaemic encephalopathy. Cochrane Database Syst Rev. 2013; (1):CD003311. PMC: 7003568. DOI: 10.1002/14651858.CD003311.pub3. View

15.

Bubenik G, Pang S . The role of serotonin and melatonin in gastrointestinal physiology: ontogeny, regulation of food intake, and mutual serotonin-melatonin feedback. J Pineal Res. 1994; 16(2):91-9. DOI: 10.1111/j.1600-079x.1994.tb00088.x. View

16.

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(2):157-64. DOI: 10.1111/j.1600-079X.2007.00503.x. View

17.

Gale C, Statnikov Y, Jawad S, Uthaya S, Modi N . Neonatal brain injuries in England: population-based incidence derived from routinely recorded clinical data held in the National Neonatal Research Database. Arch Dis Child Fetal Neonatal Ed. 2017; 103(4):F301-F306. PMC: 6047140. DOI: 10.1136/archdischild-2017-313707. View

18.

Davidson J, Yuill C, Zhang F, Wassink G, Bennet L, Gunn A . Extending the duration of hypothermia does not further improve white matter protection after ischemia in term-equivalent fetal sheep. Sci Rep. 2016; 6:25178. PMC: 4848549. DOI: 10.1038/srep25178. View

19.

Ahmed J, S A, Robertson N, More K . Melatonin for neuroprotection in neonatal encephalopathy: A systematic review & meta-analysis of clinical trials. Eur J Paediatr Neurol. 2021; 31:38-45. DOI: 10.1016/j.ejpn.2021.02.003. View

20.

Carloni S, Favrais G, Saliba E, Albertini M, Chalon S, Longini M . Melatonin modulates neonatal brain inflammation through endoplasmic reticulum stress, autophagy, and miR-34a/silent information regulator 1 pathway. J Pineal Res. 2016; 61(3):370-80. DOI: 10.1111/jpi.12354. View