Hypoxic-ischemic brain injury in the newborn: Cellular mechanisms and potential strategies for neuroprotection

Recent advances have delineated many of the complex cellular mechanisms of cerebral hypoxic-ischemic injury. These developments have created opportunities for the design of rational “mechanism-based” strategies that target specific injurious processes. A number of neuroprotective agents have entered adult clinical trial and practice. For the newborn infant, progress in this areas has been judiciously delayed by toxicity concerns. Central to those safety concerns is the close relationship between mechanisms of hypoxic-ischemic cellular injury and normal developmental processes. These cellular mechanisms and the dilemmas facing the advance of this field are discussed. The likelihood of an effective single “magic bullet” neuroprotective strategy emerging in the near future appears remote. Rather more likely is the development of “cocktail” therapies that seek to exploit synergistic antagonism at multiple levels in the complex concentration of cellular events mediating hypoxic-ischemic cellular injury. However, such combination therapies will require elucidation of the complex inter-relationships between mechanisms of cellular injury, brain development, and the combination of therapies envisioned.