Figure 1.

The Evolution of Brain Injury, Pathophysiology and the Neuroprotective Action of Melatonin. Characteristic phases (primary, latent, secondary and tertiary) of brain injury occurs following hypoxia-ischemia. These phases can be measured using proton (¹H) and phosphorus magnetic resonance spectroscopy. After the primary insult and a period of recovery in the latent phase, secondary energy failure occurs (characterised by a secondary rise in Lactate to N-acetyl aspartate (Lac/NAA) peak ratio on ¹H MRS) in parallel with the neurotoxic cascades of cellular injury. The pathological processes are multifactorial—including oxidative stress, activation of cell death pathways, neuro-inflammation, and mitochondrial failure. The neuroprotective action of melatonin is diverse. To harness its strong antioxidant properties, supra-physiological melatonin levels (15–30 mg/L) are needed early in the neurotoxic cascade. Complementary therapies including stem cells and erythropoietin targeting the tertiary phase of injury may further improve outcomes in combination with melatonin for infants with NE.