Despite the introduction of therapeutic hypothermia, neonatal hypoxic ischemic (HI) brain injury remains a common cause of developmental disability. Development of rational adjuvant therapies to hypothermia requires understanding of the pathways of cell death and survival modulated by HI. The conceptualization of the apoptosis-necrosis “continuum” in neonatal brain injury predicts mechanistic interactions between cell death and hydrid forms of cell death such as programmed or regulated necrosis. Many of the components of the signaling pathway regulating programmed necrosis have been studied previously in models of neonatal HI. In some of these investigations, they participate as part of the apoptotic pathways demonstrating clear overlap of programmed death pathways. Receptor interacting protein (RIP)-1 is at the crossroads between types of cellular death and survival and RIP-1 kinase activity triggers formation of the necrosome (in complex with RIP-3) leading to programmed necrosis. Neuroprotection afforded by the blockade of RIP-1 kinase following neonatal HI suggests a role for programmed necrosis in the HI injury to the developing brain. Here, we briefly review the state of the knowledge about the mechanisms behind programmed necrosis in neonatal brain injury recognizing that a significant proportion of these data derive from experiments in cultured cell and some from in vivo adult animal models. There are still more questions than answers, yet the fascinating new perspectives provided by the understanding of programmed necrosis in the developing brain may lay the foundation for new therapies for neonatal HI. 1. Introduction Neonatal hypoxic-ischemic encephalopathy (HIE) is a significant cause of mortality and morbidity in the pediatric population [1]. The therapeutic options for neonatal HIE are limited in part because the mechanisms of cellular degeneration in the immature brain are not fully understood. These mechanisms resulting from ischemia-reperfusion, oxidative stress, excitotoxicity and inflammation among others, activate or coactivate multiple pathways of cell death. Although, necrosis was initially described as the most prominent form of cellular degeneration following neonatal hypoxia-ischemia (HI) [2, 3], research emphasis switched to the study of apoptosis (programmed cell death type I) and autophagy largely due to advances in cell biology and to experimental animal studies on the molecular dissection of pathways for apoptotic and autophagocytic initiation and execution. The significance of necrosis in neonatal HI has been difficult to
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