Table 2 Experimental studies of prenatal melatonin supplementation in ovine models of IUGR and chronic hypoxia
From: Neonatal lamb mortality: major risk factors and the potential ameliorative role of melatonin
Publication | Methodology | Melatonin dose rate/timing | Fetal/neonatal outcomes |
|---|---|---|---|
Tare et al. (Study 1) [59] | • Induced IUGR (twins): SUAL at gD105–110 in one fetus only (other twin fetus constituted control) • Fetal femoral artery catheterised • 7 d after SUAL: Fetuses removed by C-section and heart function assessed ex vivo (Langendorff apparatus) | • IV to ewe: 2 mg bolus dose at 5 d after SUAL + 2 mg/h (48 mg/d) until post-mortem • Treatments:  - Control (sham SUAL)  - Control (sham SUAL) + MEL  - SUAL  - SUAL + MEL | In SUAL + MEL lambs compared with SUAL: • Mitigated growth restriction (93% of control weight vs. 75% of control weight) • Normalised fetal arterial O2 saturation and PO2 • Significantly increased basal coronary flow vs. control • Prevented 3-fold increase to ischaemia-reperfusion-induced infarct area in heart • Enhanced contractile function in right ventricle |
Tare et al. (Study 2) [59] | • Induced IUGR (singletons): SUAL at gD105–110 • Fetal femoral artery catheterised and blood samples taken from 5 d after SUAL to gD140 • Ewes allowed to deliver naturally at term • Lamb hearts collected for analysis 24 h post-partum | • IV to ewe: 0.25 mg/h (6 mg/d) continuously from SUAL until term • Treatments:  - Control (untreated)  - Control + MEL  - SUAL  - SUAL + MEL | In SUAL + MEL lambs compared with SUAL: • Normalised fetal arterial O2 saturation and PO2 • Normalised NO bioavailability in coronary arteries • Induced indomethacin-sensitive vasodilation in coronary arteries • Prevented stiffening of coronary arteries |
Polglase et al. [60] | • Induced IUGR: SUAL at gD105 • Fetal femoral artery catheterised and blood samples taken from 5 d after SUAL to gD145 • Ewes delivered naturally at term • Lamb lungs collected for analysis 24 h post-partum | • IV to ewe: 1 mg bolus 4 h after surgery + continuous infusion until term (6 mg/d) • Treatments:  - Control (sham SUAL)  - SUAL  - SUAL + MEL | In SUAL + MEL lambs compared with controls and SUAL: • Reduced birthweight (3.17 ± 0.20 kg) vs. control (4.51 ± 0.24 kg) but not SUAL (3.08 ± 0.47 kg) • Prevented chronic hypoxia (similar to controls) • Similarly compromised lung structure (reduced secondary septal crest density and altered elastin deposition) as SUAL vs. control |
Castillo-Melendez et al. [61] | • Induced IUGR: SUAL at gD105 • Ewes delivered naturally at term • Lamb brains collected for analysis 24 h post-partum | • IV to ewe: 1 mg bolus 4 h after SUAL + continuous infusion (6 mg/d) until term • Treatments:  - Control (sham SUAL)  - Control (sham SUAL) + MEL  - SUAL  - SUAL + MEL | In SUAL + MEL lambs compared with controls and SUAL: • Fewer laminin-positive blood vessel in subcortical and periventricular white matter vs. controls • Greater endothelium glucose transporter-1 immunoreactivity vs. SUAL (similar to controls) • Normalised pericyte coverage and astrocyte attachment to blood vessels vs. SUAL • Normalised apoptotic blood vessel number vs. SUAL • Prevented disruption of blood-brain barrier |
Miller et al. [43] | • Induced IUGR: SUAL at gD105–110 • Fetal femoral artery catheterised and blood samples taken from 5 d after SUAL to gD145 • Ewes allowed to deliver naturally • Lambs brains collected for analysis 24 h post-partum | • IV to ewe: 1 mg bolus dose 4 h after surgery + IV infusion of 0.25 mg/h (6 mg/d) until delivery • Treatments:  - Control (sham SUAL)  - SUAL  - SUAL + MEL | In SUAL + MEL lambs compared with SUAL: • Lower latency to stand and suckle after birth • Ameliorated oxidative stress, normalised myelination, and rescued axonopathy in brain |
González-Candia et al. [62] | • Ewes subjected to chronic hypobaric hypoxia (altitude 3600 m) from pre-conception until end experiment • Ewes allowed to deliver naturally at term | • Oral to ewe: 10 mg/kg daily at 18:00 h from gD100 until term • Treatments:  - Untreated IUGR (EtOH vehicle)  - IUGR + MEL | In IUGR + MEL lambs compared with untreated IUGR: • Lower birthweight (2.88 ± 0.22 kg vs. 3.56 ± 0.16 kg) • Smaller biparietal diameter, crown-rump length, and abdominal diameter at birth |
Gonzalez-Candia et al. [63] | • Ewes subjected to chronic hypobaric hypoxia (altitude 3600 m) from pre-conception until end experiment • Ewes delivered naturally at term • Lamb’s pulmonary artery catheterised 2 d post-partum • Lamb lungs collected for analysis at 12 d post-partum | • Oral to ewe: 10 mg/d from gD100 until term • Treatments:  - Control (EtOH vehicle)  - MEL | In MEL lambs compared with controls: • Lower birthweight (3.45 ± 0.36 kg vs. 4.90 ± 0.44 kg) • Lower biparietal diameter at birth, but recovered by 7 d post-partum • Higher plasma antioxidant capacity and lower pulmonary antioxidant activity • Lower ROS generation in lungs |