Table 1 Experimental studies of neonatal melatonin supplementation in ovine models of prenatal or neonatal hypoxia

Herrera et al. [53]

• Ewes subjected to chronic hypobaric hypoxia (altitude 3600 m) from pre-conception until end experiment

• Graded oxygenation protocol to assess acute neonatal responses to oxygen concentration (controlled gas levels in polyethylene bag over lamb’s head) after 7 d melatonin treatment

• Tissue collected for analysis 12 d post-partum

• Oral to lamb: 1 mg/kg daily at 18:00 h from d 4–12 post-partum

• Treatments:

 - Control (EtOH vehicle)

 - MEL

In MEL lambs compared with controls:

• Greater fractional growth during first 3 d of treatment

• Greater carotid bloodflow at all PO₂ levels

• Improved vascular responses to potassium, serotonin, methacholine, and melatonin itself

• Improved endothelial response in isolated middle cerebral arteries via NO-independent mechanisms

• Lower oxidative stress (nitrotyrosine) level in middle cerebral arteries

Astorga et al. [54]

• Ewes subjected to chronic hypobaric hypoxia (altitude 3600 m) from pre-conception until end experiment

• Graded oxygenation protocol (controlled gas levels in polyethylene bag over lamb’s head) to assess acute neonatal responses to oxygen concentration after 7 d melatonin treatment

• Tissue collected for analysis 12 d post-partum

• Oral to lamb: 1 mg/kg daily at 20:00 h from d 3–12 post-partum

• Treatments:

 - Control (EtOH vehicle)

 - MEL

In MEL lambs compared with controls:

• Reduced pulmonary pressor response to graded oxygenation changes

• Reduced pulmonary level of pathological vascular remodelling markers (α-actin, smoothelin-B)

• Greater vascular density and luminal surface area of small pulmonary arteries

• Reduced oxidative stress (nitrotyrosine) level in small pulmonary vessels

Gonzaléz-Candia et al. [55]

• Ewes subjected to chronic hypobaric hypoxia (altitude 3600 m) from pre-conception until end experiment

• Tissue collected for analysis 29 d post-partum

• Oral to lamb: 1 mg/kg daily at 20:00 h from d 4–21 post-partum

• Treatments:

 - Control (EtOH vehicle)

 - MEL

In MEL lambs compared with controls:

• Lower pulmonary artery pressure for first 4 d of treatment.

• Reduced contractile response to vasoconstrictors (K⁺, thromboxane synthase, endothelin)

• Enhanced endothelium-dependent and muscle-dependent vasodilation in small pulmonary arteries

• Reduced pulmonary oxidative stress markers (4-hydroxynonenal and nitrotyrosine)

Aridas et al. [56]

• Acute hypoxia: UCO at birth until blood pressure reached 18–20 mmHg

• Brain magnetic resonance spectroscopy at 12 and 72 h post-partum

• Lambs euthanased 72 h post-partum and tissue collected for analysis

• IV to lamb: 5 mg bolus 30 min post-partum + 5 mg every 2 h for 24 h (total 60 mg), or

• 5 mg transdermal patch to lamb: 6 patches 30 min post-partum + 6 patches 12 h post-partum (total 60 mg)

• Treatments:

 - Control (untreated)

 - Control + MEL

 - UCO

 - UCO + MEL (IV)

 - UCO + MEL-P (patch)

In UCO + MEL (IV) and UCO + MEL-P lambs compared with UCO:

• Prevented 2.5–3-fold increase to magnetic resonance spectroscopy lactate: N-acetyl aspartate ratio

• Attenuated grey and white matter apoptotic cell death, lipid peroxidation, and neuroinflammation

• Lower latency to stand and suckle after birth, greater proportion of lambs standing and suckling, and reduced prevalence of seizures in asphyxiated lambs