Journal
JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM
Volume 31, Issue 1, Pages 178-189Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/jcbfm.2010.72
Keywords
apoptosis-necrosis cell death continuum; cytokines; delayed neurodegeneration; NF kappa B; programmed necrosis; receptor-interacting protein (RIP)
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Funding
- March of Dimes Foundation [(6-08-275) NS 059529, AG016282]
- Lehmann Brothers Foundation
- NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE [R01NS045059, R21NS059529] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE ON AGING [R01AG016282] Funding Source: NIH RePORTER
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Necrostatin-1 inhibits receptor-interacting protein (RIP)-1 kinase and programmed necrosis and is neuroprotective in adult rodent models. Owing to the prominence of necrosis and continuum cell death in neonatal hypoxia-ischemia (HI), we tested whether necrostatin was neuroprotective in the developing brain. Postnatal day (P) 7 mice were exposed to HI and injected intracerebroventricularly with 0.1 mu L of 80 mu mol necrostatin, Nec-1, 5-(1H-Indol-3-ylmethyl)-(2-thio-3-methyl) hydantoin, or vehicle. Necrostatin significantly decreased injury in the forebrain and thalamus at P11 and P28. There was specific neuroprotection in necrostatin-treated males. Necrostatin treatment decreased necrotic cell death and increased apoptotic cell death. Hypoxia-ischemia enforced RIP1-RIP3 complex formation and inhibited RIP3-FADD (Fas-associated protein with death domain) interaction, and these effects were blocked by necrostatin. Necrostatin also decreased HI-induced oxidative damage to proteins and attenuated markers of inflammation coincidental with decreased nuclear factor-kappa B and caspase 1 activation, and FLIP ((Fas-associated death-domain-like IL-1 beta-converting enzyme)-inhibitory protein) gene and protein expression. In this model of severe neonatal brain injury, we find that cellular necrosis can be managed therapeutically by a single dose of necrostatin, administered after HI, possibly by interrupting RIP1-RIP3-driven oxidative injury and inflammation. The effects of necrostatin treatment after HI reflect the importance of necrosis in the delayed phases of neonatal brain injury and represent a new direction for therapy of neonatal HI. Journal of Cerebral Blood Flow & Metabolism (2011) 31, 178-189; doi:10.1038/jcbfm.2010.72; published online 23 June 2010
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