New knowledge of the pathophysiology and evolution of hypoxic-ischemic brain 
injuries has made feasible interventions to improve clinical outcomes for 
newborns surviving birth asphyxia. Brain injury following hypoxic-ischemic 
insult is a complex process evolving over hours to days, which provides a unique 
window of opportunity for neuroprotective treatment interventions. The specific 
pathologic processes preceding the onset of irreversible cerebral injury appear 
to be a combination of several mechanisms that are variable according to the 
severity and duration of the insult and to biochemical modifications in the 
brain. Advances in neuroimaging, brain monitoring techniques, and tissue 
biomarkers have improved the ability to diagnose, monitor, and care for newborn 
infants with neonatal encephalopathy, as well as to predict their outcome. The 
role of oxidative stress in newborn morbidity with respect to the higher risk of 
free radical damage in these babies is growing. However, challenges remain in 
early identification of infants at risk for neonatal encephalopathy, 
determination of timing and extent of hypoxic-ischemic brain injury, as well as 
optimal management and treatment duration. Potential neuroprotective strategies 
targeting different pathways leading to neuronal cell death in response to 
hypoxic-ischemic insult have been investigated: hypothermia, erythropoietin, 
iminobiotin, deferioxamine, magnesium, allopurinol, xenon, melatonin and 
statins. Hypothermia is currently the only recognized beneficial therapy. 
However, many infants still develop significant adverse outcomes. It is becoming 
evident that the association of moderate hypothermia with neuroprotective drugs 
may enhance the outcome. By virtue of their pleiotropic effects without toxic 
effects, melatonin and statins may act at different levels of the multiple 
mechanisms responsible for the progression of the neurodegenerative process and 
represent promising neuroprotectants, alone or as additional adjunctive therapy, 
for reducing brain injury and its long-term sequelae in infants. More clinical 
studies are needed to clarify the role of these potential neuroprotective drugs.