ABSTRACT
Therapeutic hypothermia protocols are now established in term and near-term babies with neonatal encephalopathy (NE). Despite treatment, however, NE infants still experience unacceptably high rates of adverse outcome. The current challenge is to find safe and complementary therapies that confer additional protection, regeneration and repair. Following intrapartum hypoxia-ischemia, brain injury evolves over three main phases (early/latent, secondary and tertiary phases), each with a different brain energy, perfusion, neurochemical, and inflammatory profile. Therapeutic hypothermia targets the latent and secondary phase, however therapies that cover the continuum of brain injury that spans hours, days, weeks, and months are required. Therapies can be broadly classified under a predominant action (e.g. free radical scavenging, anti-apoptotic effects, anti-inflammatory effects, neuroregeneration, and vascular effects). Promising early/secondary phase therapies include Azithromycin, Magnesium, Melatonin, Noble gases. Tertiary phase agents include Erythropoietin and Stem cells. We review a selection of promising therapeutic agents on the translational pipeline and suggest a framework for future pre-clinical studies of neuroprotection and neurorestoration. Fine-tuning neuroprotection will require targeted therapies in all phases with a particular focus on neuroregeneration, immunomodulation and neurorestoration in the tertiary phase. Clinically relevant surrogate outcome measures are needed to speed up clinical trial read-outs.
