Melatonin for Neonatal Encephalopathy: From Bench to Bedside

Pang, Raymand; Advic-Belltheus, Adnan; Meehan, Christopher; Fullen, D; Golay, Xavier; Robertson, Nicola J.

doi:10.3390/ijms22115481

Cited by 13 publications

(13 citation statements)

References 163 publications

(233 reference statements)

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“…The mechanisms of action of melatonin are multifaceted, including anti-apoptotic properties, anti-inflammatory, the reduction of oxidative stress and receptor mediated effects through melatonin receptor (MT)1, MT2, and MT3. Melatonin dampens down the NLRP3 inflammasome and can block TLR4 signalling and NfkB and this may prove integral in infants with NE [30].…”

Section: Discussionmentioning

confidence: 99%

Melatonin Alters Innate Immune Function in Infants with Neonatal Encephalopathy

Aslam¹,

O’Dea²,

Kelly³

et al. 2023

Neonatology

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Introduction: Melatonin has been suggested an adjunctive therapy in neonatal encephalopathy (NE). Melatonin reduces oxidative stress and neutrophil activation; however, the immunological effects in NE have not been studied. Methods: Infants with NE and neonatal controls were prospectively recruited. Whole blood was sampled in the first week of life. Following endotoxin and or melatonin treatment, diurnal variation was measured by RT PCR for circadian rhythm genes (brain and Muscle Arnt-Like protein [BMAL1], circadian locomotor output cycles kaput [CLOCK], Nuclear Receptor Subfamily 1 Group D Member 2 [REV Erβ], and cryptochrome circadian clock [CRY]). Neutrophil and monocyte cell surface markers of activation CD11b, reactive oxygen intermediates (ROIs), and Toll-like receptor (TLR)-4 were also examined by flow cytometry in matching samples. Results: Serum and RNA samples from forty infants were included (controls n = 20; NE n = 20) over the first week of life. Melatonin reduced neutrophil CD11b and TLR-4 expression in response to LPS in infants with NE compared to controls. There were no differences in ROIs. BMAL1 and CLOCK baseline gene expression levels were similar. BMAL1 was significantly decreased with LPS stimulation in NE. There was no significant diurnal variation in melatonin, neutrophil, and monocyte function or circadian genes. Conclusions: Melatonin alters immune function ex vivo in infants with NE. Infants with NE have altered immune circadian responses following LPS stimulation, which have potential for modulation.

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Section: Discussionmentioning

confidence: 99%

Melatonin Alters Innate Immune Function in Infants with Neonatal Encephalopathy

Aslam¹,

O’Dea²,

Kelly³

et al. 2023

Neonatology

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“…The only adult study that tested post-insult treatment administered creatine into the brain via intracerebroventricular infusion 30 min after HI and reported a reduction in hippocampal injury but no improvement in sensory-motor function [ 29 ]. The mechanisms underlying cell death, which occur during or very soon after HI, are different from those that occur in the hours, days, and weeks after the insult [ 61 , 62 ]. Therefore, any effects arising from pre-treatment or immediate post-insult treatment do not necessarily indicate the treatment will be effective if the injury had already started to evolve.…”

Section: Discussionmentioning

confidence: 99%

“…Whether prophylactically treating all pregnancies with creatine is a safe and pragmatic option is in the early phase of clinical trials (ACTRN12620001373965). Pharmacological interventions for HIE need to be administered around the time of bulk cell death, which occurs within hours to days after the insult, to maximize their neuroprotective efficacy [ 54 , 61 , 62 , 65 , 66 ]. Collectively, these data indicate that we must further improve our understanding of the therapeutic window that is most likely to demonstrate benefit, in carefully designed preclinical studies, before progressing creatine further down the translational pipeline.…”

Section: Discussionmentioning

confidence: 99%

Assessing Creatine Supplementation for Neuroprotection against Perinatal Hypoxic-Ischaemic Encephalopathy: A Systematic Review of Perinatal and Adult Pre-Clinical Studies

Tran

Kelly

Snow

et al. 2021

Cells

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There is an important unmet need to develop interventions that improve outcomes of hypoxic-ischaemic encephalopathy (HIE). Creatine has emerged as a promising neuroprotective agent. Our objective was to systematically evaluate the preclinical animal studies that used creatine for perinatal neuroprotection, and to identify knowledge gaps that need to be addressed before creatine can be considered for pragmatic clinical trials for HIE. Methods: We reviewed preclinical studies up to 20 September 2021 using PubMed, EMBASE and OVID MEDLINE databases. The SYRCLE risk of bias assessment tool was utilized. Results: Seventeen studies were identified. Dietary creatine was the most common administration route. Cerebral creatine loading was age-dependent with near term/term-equivalent studies reporting higher increases in creatine/phosphocreatine compared to adolescent-adult equivalent studies. Most studies did not control for sex, study long-term histological and functional outcomes, or test creatine post-HI. None of the perinatal studies that suggested benefit directly controlled core body temperature (a known confounder) and many did not clearly state controlling for potential study bias. Conclusion: Creatine is a promising neuroprotective intervention for HIE. However, this systematic review reveals key knowledge gaps and improvements to preclinical studies that must be addressed before creatine can be trailed for neuroprotection of the human fetus/neonate.

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“…Pharmacokinetic modelling in piglets indicates that a dose of 20–30 mg/kg intravenous for 2 h repeated 24 h later is required to maintain a therapeutic concentration of 15–30 mg/L [ 52 ]. Detailed pharmacokinetic studies are required in neonates with moderate and severe HIE before a dosing regimen is determined.…”

Section: Melatoninmentioning

confidence: 99%

New possibilities for neuroprotection in neonatal hypoxic-ischemic encephalopathy

et al. 2021

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Around 0.75 million babies worldwide suffer from moderate or severe hypoxic-ischemic encephalopathy (HIE) each year resulting in around 400,000 babies with neurodevelopmental impairment. In 2010, neonatal HIE was associated with 2.4% of the total Global Burden of Disease. Therapeutic hypothermia (TH), a treatment that is now standard of care in high-income countries, provides proof of concept that strategies that aim to improve neurodevelopment are not only possible but can also be implemented to clinical practice. While TH is beneficial, neonates with moderate or severe HIE treated with TH still experience devastating complications: 48% (range: 44–53) combined death or moderate/severe disability. There is a concern that TH may not be effective in low- and middle-income countries. Therapies that further improve outcomes are desperately needed, and in high-income countries, they must be tested in conjunction with TH. We have in this review focussed on pharmacological treatment options (e.g. erythropoietin, allopurinol, melatonin, cannabidiol, exendin-4/exenatide). Erythropoietin and allopurinol show promise and are progressing towards the clinic with ongoing definitive phase 3 randomised placebo-controlled trials. However, there remain global challenges for the next decade. Conclusion: There is a need for more optimal animal models, greater industry support/sponsorship, increased use of juvenile toxicology, dose-ranging studies with pharmacokinetic-pharmacodynamic modelling, and well-designed clinical trials to avoid exposure to harmful medications or abandoning putative treatments. What is Known:• Therapeutic hypothermia is beneficial in neonatal hypoxic-ischemic encephalopathy.• Neonates with moderate or severe hypoxic-ischemic encephalopathy treated with therapeutic hypothermia still experience severe sequelae. What is New:• Erythropoietin, allopurinol, melatonin, cannabidiol, and exendin-4/exenatide show promise in conjunction with therapeutic hypothermia.• There is a need for more optimal animal models, greater industry support/sponsorship, increased use of juvenile toxicology, dose-ranging studies with pharmacokinetic-pharmacodynamic modelling, and well-designed clinical trials.

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Melatonin for Neonatal Encephalopathy: From Bench to Bedside

Cited by 13 publications

References 163 publications

Melatonin Alters Innate Immune Function in Infants with Neonatal Encephalopathy

Melatonin Alters Innate Immune Function in Infants with Neonatal Encephalopathy

Assessing Creatine Supplementation for Neuroprotection against Perinatal Hypoxic-Ischaemic Encephalopathy: A Systematic Review of Perinatal and Adult Pre-Clinical Studies

New possibilities for neuroprotection in neonatal hypoxic-ischemic encephalopathy

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