Table 3 Experimental studies of prenatal melatonin supplementation in ovine models of acute hypoxia

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