Melatonin augments the neuroprotective effects of hypothermia in lambs following perinatal asphyxia.
brain injury
melatonin
neonatal encephalopathy
neuroprotection
oxidative stress
perinatal asphyxia
therapeutic hypothermia
Journal
Journal of pineal research
ISSN: 1600-079X
Titre abrégé: J Pineal Res
Pays: England
ID NLM: 8504412
Informations de publication
Date de publication:
Aug 2021
Aug 2021
Historique:
revised:
19
05
2021
received:
22
03
2021
accepted:
20
05
2021
pubmed:
26
5
2021
medline:
29
12
2021
entrez:
25
5
2021
Statut:
ppublish
Résumé
Therapeutic hypothermia (TH) is standard care in high-resource birth settings for infants with neonatal encephalopathy. TH is partially effective and adjuvant therapies are needed. Here, we examined whether the antioxidant melatonin (MLT) provides additive benefit with TH, compared to TH alone or MLT alone, to improve recovery from acute encephalopathy in newborn lambs. Immediately before cesarean section delivery, we induced asphyxia in fetal sheep via umbilical cord occlusion until mean arterial blood pressure fell from 55 ± 3 mm Hg in sham controls to 18-20 mm Hg (10.1 ± 1.5 minutes). Lambs were delivered and randomized to control, control + MLT (60 mg iv, from 30 minutes to 24 hours), asphyxia, asphyxia + TH (whole-body cooling to 35.1 ± 0.8°C vs. 38.3 ± 0.17°C in sham controls, from 4-28 hours), asphyxia + MLT, and asphyxia + TH + MLT. At 72 hours, magnetic resonance spectroscopy (MRS) was undertaken, and then brains were collected for neuropathology assessment. Asphyxia induced abnormal brain metabolism on MRS with increased Lactate:NAA (P = .003) and reduced NAA:Choline (P = .005), induced apoptotic and necrotic cell death across gray and white matter brain regions (P < .05), and increased neuroinflammation and oxidative stress (P < .05). TH and MLT were independently associated with region-specific reductions in oxidative stress, inflammation, and cell death, compared to asphyxia alone. There was an interaction between TH and MLT such that the NAA:Choline ratio was not significantly different after asphyxia + TH + MLT compared to sham controls but had a greater overall reduction in neuropathology than either treatment alone. This study demonstrates that, in newborn lambs, combined TH + MLT for neonatal encephalopathy provides significantly greater neuroprotection than either alone. These results will guide the development of further trials for neonatal encephalopathy.
Substances chimiques
Neuroprotective Agents
0
Melatonin
JL5DK93RCL
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
e12744Subventions
Organisme : National Health and Medical Research Council (NHMRC) of Australia
Organisme : Victorian Government's Operational Infrastructure Support Program
Organisme : Bill and Melinda Gates Foundation
Informations de copyright
© 2021 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
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