Perinatal brain injury: mechanisms and therapeutic approaches

Brain damage resulting from perinatal hypoxia-ischemia evolves slowly over time. While a small number of brain cells may die during a sufficiently profound period of hypoxia-ischemia, many will show initial recovery during a "latent" phase characterized by actively suppressed neural metabolism and activity. Critically, this transient recovery may be followed after ~6 hours by a phase of secondary deterioration, with delayed seizures, failure of mitochondrial function, cytotoxic edema, and bulk cell death over ~72 hours. This is followed by a tertiary phase of remodeling and recovery. Understanding the mechanisms of injury that occur during each phase may allow for the development of more targeted treatments. This review discusses the mechanisms of injury that occur during the primary, latent, secondary and tertiary phases of injury and potential treatments that target one or more of these phases. Treatment during the latent phase has the greatest potential to prevent injury. In the secondary phase of injury, anticonvulsants can attenuate seizures but show limited neuroprotection. By contrast, there is increasing preclinical evidence that neurorestorative therapies may improve long-term outcomes.