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Neurology Research International
Volume 2012, Article ID 257563, 12 pages
http://dx.doi.org/10.1155/2012/257563
Review Article

Programmed Necrosis: A Prominent Mechanism of Cell Death following Neonatal Brain Injury

1Neonatal Research Laboratory, Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD 21287-3200, USA
2Division of Neonatology, Texas Tech University Health Sciences Center, Odessa, TX 79763, USA
3Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21287-3200, USA
4Division of Neuropathology, Johns Hopkins University School of Medicine, Baltimore, MD 21287-3200, USA
5Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21287-3200, USA

Received 28 November 2011; Accepted 2 February 2012

Academic Editor: Jianrong Li

Copyright © 2012 Raul Chavez-Valdez et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

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.