The advantages and limitations of animal models for understanding acute neonatal brain injury

Neonatal hypoxic-ischemic encephalopathy (HIE) remains a major cause of death and disability around the world. Therapeutic hypothermia is now established to improve outcomes in term and near-term infants in high-income countries, but even in this setting, many infants still survive with disability. To further improve outcomes, experimental models are needed to test new interventions before clinical translation. In the present review, we discuss the strengths and weaknesses of a range of near-term and term models and their utility for understanding the pathophysiology of HIE and to test potential treatments. It is important to reflect that the strength of the evidence base for therapeutic hypothermia before it went to trial was that multiple groups using different and complementary models all showed benefit and that these models had been used to define the key parameters needed to achieve neuroprotection. We strongly advocate that this should be the expectation for all new neuroprotective interventions before large pragmatic randomized controlled trials are carried out.