Efficacy of melatonin in term neonatal models of perinatal hypoxia‐ischaemia

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 À2.05, 95% CI [À2.93, À1.16]), improved neurobehavioural outcomes (SMD À0.86, 95% CI [À1.23, À0.53]) and reduction in cell death (SMD À0.60, 95% CI [À1.06, À0.14]) 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.

Melatonin: A Potential Candidate for the Treatment of Experimental and Clinical Perinatal Asphyxia

“…A meta-analysis showed the neuroprotective effects of melatonin in experimental models of hypoxic-ischemic encephalopathy by reducing neuronal death and improving neurobehavioral and neurological outcomes ( Figure 1 ) [ 133 ]. In addition, animal studies have indicated that melatonin may ameliorate Alzheimer’s disease-related alterations in amyloid, tau protein and neurotransmission ( Figure 1 ).…”

“…The neuroprotective effects of melatonin have been present in single therapy as well as in combination with hypothermia [ 133 ]. The analysis of the studied subgroups showed greater effectiveness after the administration of melatonin before or immediately after the injury and with ethanol auxiliaries [ 133 ].…”

“…The neuroprotective effects of melatonin have been present in single therapy as well as in combination with hypothermia [ 133 ]. The analysis of the studied subgroups showed greater effectiveness after the administration of melatonin before or immediately after the injury and with ethanol auxiliaries [ 133 ]. Despite the abundance of experimental data supporting the role of melatonin as a neuroprotective substance in hypoxic-ischemic encephalopathy, both alone and in addition to hypothermia, clinical evidence for neuroprotective effects in neonates after perinatal asphyxia is very limited.…”

“…In another study, piglets showed faster EEG amplitude recovery between 25 and 30 h with melatonin (i.v.) plus hypothermia ( Table 2 ) [ 133 ]. The lactate/aspartate peak ratio was lower after about 3 days with melatonin (i.v.)…”

“…The lactate/aspartate peak ratio was lower after about 3 days with melatonin (i.v.) plus hypothermia [ 133 ]. Dual therapy reduced the number of TUNEL-positive neurons in the sensory cortex and improved the survival of oligodendrocytes in the hippocampus and periventricular white matter, and increased the immunoreactivity of astrocytes in the hippocampus and periventricular white matter ( Table 2 ) [ 133 ].…”