Table 3.

Experimental studies of prenatal melatonin supplementation in ovine models of acute hypoxia

Publication	Methodology	Melatonin dose rate/timing	Fetal/lamb outcomes
Miller et al. [45]	• Induced fetal asphyxia: 10 min UCO at gD124–127 • Probes fitted to fetal brains • Fetal brains collected for analysis 48 h after UCO	• IV to ewe: 1 mg bolus + 1 mg/h for 2 h only • Treatments:  - Sham + vehicle (EtOH)  - UCO + vehicle  - UCO + MEL	In UCO + MEL fetuses compared with UCO + vehicle: • Prevention of 60–90 min •OH spikes observed in grey matter of UCO + vehicle fetuses immediately after UCO and 8–9.5 h after UCO • Significantly reduced lipid peroxidation in cortical white matter, thalamus/hypothalamus, and subcallosal bundle
Drury et al. [82]	• Induced fetal asphyxia: 25 min UCO at gD101–104 • Fetal brains collected for analysis 7 d after UCO	• IV to ewe: 0.1 mg/kg bolus 15 min before UCO + 0.1 mg/kg/h for 6 h • Treatments:  - Sham UCO  - UCO + saline  - UCO + vehicle (EtOH)  - UCO + MEL	In UCO + MEL fetuses compared with UCO + saline and UCO + vehicle: • Significantly faster electroencephalogram recovery vs. UCO + saline • Delayed onset of seizures • Greater number of mature oligodendrocytes (similar level as sham UCO) • Reduced microglial activation in white matter
Yawno et al. [83]	• Induced fetal asphyxia: 10 min UCO at ~gD130 • Fetal brains collected for analysis 48 h after UCO	• IV to ewe: 1 mg bolus 1 h before UCO + 2 mg/h for 2 h (total 5 mg) • Treatments:  - Sham UCO + vehicle (EtOH)  - UCO + vehicle (EtOH)  - UCO + MEL	In UCO + MEL fetuses compared with UCO + vehicle: • Ameliorated pyknotic cell death in hippocampus (>  7-fold) and cerebellum (3-fold) • Prevention of astrogliosis, albumin uptake increases, microglial activation and lipid peroxidation in brain
Welin et al. [84]	• Induced fetal asphyxia: 23.5 min UCO at gD91–93 • Fetal brains collected for analysis 4 d after UCO	• IV to fetus: 20 mg/kg hourly from 10 min after UCO for 6 h • Treatments:  - UCO + EtOH vehicle  - UCO + MEL	In UCO + MEL fetuses compared with UCO + EtOH vehicle: • Attenuated increase of oxidative stress (8-isoprostane) in serum • Fewer apoptotic (TUNEL-positive) cells in subcortical white matter and thalamus • Fewer activated microglial cells in white matter
Yawno et al. [85]	• Induced fetal asphyxia: 25 min UCO at gD102 • Fetal femoral artery + vein catheterised • Fetal brains collected for analysis 10 d after UCO	• IV to fetus: 0.2 mg bolus 2 h after UCO + 0.1 mg/h for next 24 h (total 2.6 mg) • Treatments:  - Control (Sham UCO + saline)  - UCO + saline  - UCO + MEL	In UCO + MEL fetuses compared with UCO + saline: • Prevented increase to white matter cell death • Reduced microglial activation (neuroinflammation) in subventricular and subcortical white matter • Prevented increase of oxidative stress (8-OHdG+) in subventricular and subcortical white matter • Normalised oligodendrocyte number in periventricular white matter • Normalised CNPase+ myelin density in subcortical white matter

UCO Umbilical cord occlusion, gD gestational day, IV Intravenous, EtOH Ethanol, MEL Melatonin, TUNEL Terminal deoxynucleotidyl transferase dUTP nick end labelling, 8-OHdG 8-hydroxy-2′-deoxyguanosine