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Melatonin augments the neuroprotective effects of hypothermia in lambs following perinatal asphyxia
Author(s) -
Aridas James DS.,
Yawno Tamara,
Sutherland Amy E.,
Nitsos Ilias,
Wong Flora Y.,
Hunt Rod W.,
Ditchfield Michael,
Fahey Michael C.,
Malhotra Atul,
Wallace Euan M.,
Gunn Alistair J.,
Jenkin Graham,
Miller Suzanne L.
Publication year - 2021
Publication title -
journal of pineal research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.881
H-Index - 131
eISSN - 1600-079X
pISSN - 0742-3098
DOI - 10.1111/jpi.12744
Subject(s) - melatonin , asphyxia , medicine , hypothermia , encephalopathy , anesthesia , neuroprotection , perinatal asphyxia , oxidative stress , neonatal encephalopathy , endocrinology
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.