Pathogenesis of hypoxic-ischemic cerebral injury in the term infant: current concepts

Multiple, biochemical cascades contribute to the pathogenesis of neonatal hypoxic-ischemic brain injury. This article summarizes experimental evidence that supports the role of excitatory amino acids, calcium, free radicals, nitric oxide, proinflammatory cytokines, and bioactive lipids. Specific vulnerabilities that distinguish the response of the immature brain from that of the mature brain are highlighted. These include increased susceptibility to excitotoxicity and free radical injury, greater tendency to apoptotic death, and heightened vulnerability of developing oligodendrocytes. Available supportive evidence from human studies is also included. implications for clinical neuroprotective strategies are discussed. Our understanding of the mechanisms of perinatal hypoxic-ischemic (HI) brain injury has increased dramatically over the past two decades. Although we once thought that there was a simple relationship between energy failure and tissue necrosis, we now know that a complex web of biochemical cascades can result in distinct modes of cell death. This article highlights recent evidence about the initiating mechanisms, subsequent mediator cascades, and final effector steps in cell death; the primary focus will be on biochemical mechanisms. Much of what has been learned about mechanisms of hypoxic-ischemic injury in the immature brain derives from studies of cerebral ischemia in adult experimental models over the past two decades. It is important to emphasize, however, that there are specific vulnerabilities that distinguish the response of the immature brain from that of the mature brain. These include increased susceptibility to excitotoxicity and free radical injury, greater tendency to apoptotic death, and heightened vulnerability of developing oligodendrocytes. Most of the data that will be highlighted in this article were obtained in immature animal models of cerebral hypoxia-ischemia; available supportive evidence form human studies is also included.