Failure to complete apoptosis following neonatal hypoxia–ischemia manifests as “continuum” phenotype of cell death and occurs with multiple manifestations of mitochondrial dysfunction in rodent forebrain

Northington, Frances J.; Zelaya, Mario Enrique; O’Riordan, Declan P.; Blomgren, Klas; Flock, Debra L.; Hagberg, Henrik; Ferriero, Donna M.; Martin, Lee J.

doi:10.1016/j.neuroscience.2007.06.060

Cited by 140 publications

(154 citation statements)

References 44 publications

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“…It is interesting to observe that some regions were better protected by one mode of treatment, probably related to different mechanistic profiles, and that the combination might improve the overall efficacy. Hypothermia has been shown to strongly reduce injury in the cerebral cortex as well as in the hippocampus (24), and apoptotic mechanisms seem to have different importance in different regions (25,26). The lack of additive effect in some regions may well be due to partly overlapping neuroprotective mechanisms, e.g., both Casp2 gene deficiency and hypothermia improve mitochondrial integrity and attenuate downstream apoptotic mechanisms (10,(21)(22)(23).…”

Section: Discussionmentioning

confidence: 99%

Combined effect of hypothermia and caspase-2 gene deficiency on neonatal hypoxic–ischemic brain injury

et al. 2012

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Articles Translational Investigation nature publishing group INTODUCTION: hypoxia-ischemia (hI) injury in term infants develops with a delay during the recovery phase, opening up a therapeutic window after the insult. hypothermia is currently an established neuroprotective treatment in newborns with neonatal encephalopathy (Ne), saving one in nine infants from developing neurological deficits. caspase-2 is an initiator caspase, a key enzyme in the route to destruction and, therefore, theoretically a potential target for a pharmaceutical strategy to prevent hI brain damage. METHODS:The aim of this study was to explore the neuroprotective efficacy of hypothermia in combination with caspase-2 gene deficiency using the neonatal Rice-Vannucci model of hI injury in mice. RESULTS: hI brain injury was moderately reduced in caspase-2 −/− mice as compared with wild-type (WT) mice. Five hours of hypothermia (33 °c ) vs. normothermia (36 °c) directly after hI provided additive protection overall (temperature P = 0.0004, caspase-2 genotype P = 0.0029), in the hippocampus and thalamus, but not in other gray matter regions or white matter. Delayed hypothermia initiated 2 h after hI in combination with caspase-2 gene deficiency reduced injury in the hippocampus, but not in other brain areas. DISCUSSION: In conclusion, caspase-2 gene deficiency combined with hypothermia provided enhanced neuroprotection as compared with hypothermia alone.

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Section: Discussionmentioning

confidence: 99%

Combined effect of hypothermia and caspase-2 gene deficiency on neonatal hypoxic–ischemic brain injury

et al. 2012

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“…The coactivation of apoptotic and necrotic cell deaths is prominent in the developing brain after hypoxia-ischemia (HI) and excitotoxicity (Northington et al, 2007;Portera-Cailliau et al, 1997).…”

Section: Introductionmentioning

confidence: 99%

“…In vitro, necrostatin has little effect on classic apoptotic cell death, but rather, strongly inhibits programmed cellular necrosis (Degterev et al, 2005). In neonatal brain HI, the prominence of necrosis and the hybrid 'continuum' cell death (Northington et al, 2007), the known role of death receptor activation (Graham et al, 2004;Northington et al, 2001a), and the importance of oxidative injury and inflammation (Barks et al, 2008;Sheldon et al, 2004) led us to test the possibility that necrostatin could inhibit these mechanisms. We tested the efficacy of necrostatin to block neurodegeneration and cell death after neonatal HI and sought to identify the possible molecular mechanisms of action.…”

Section: Introductionmentioning

confidence: 99%

Necrostatin Decreases Oxidative Damage, Inflammation, and Injury after Neonatal HI

Northington

Chavez‐Valdez

Graham

et al. 2010

J Cereb Blood Flow Metab

192

194

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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 lL of 80 lmol 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-jB and caspase 1 activation, and FLIP ((Fas-associated death-domain-like IL-1b-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.

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“…1 While the ischemic core consists mainly of dead (necrotic and apoptotic) or irreversibly dying tissues, the 'stunned' penumbra is composed of potentially recoverable tissues. [2][3][4] Being able to identify, quantify, and reliably determine such salvageable tissue is pivotal to any effective and safe intervention.…”

Section: Introductionmentioning

confidence: 99%

Automated Core–Penumbra Quantification in Neonatal Ischemic Brain Injury

Ghosh

Yuan

Turenius

et al. 2012

J Cereb Blood Flow Metab

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Neonatal hypoxic-ischemic brain injury (HII) and arterial ischemic stroke (AIS) result in irreversibly injured (core) and salvageable (penumbral) tissue regions. Identification and reliable quantification of salvageable tissue is pivotal to any effective and safe intervention. Magnetic resonance imaging (MRI) is the current standard to distinguish core from penumbra using diffusionperfusion mismatch (DPM). However, subtle MR signal variations between core-penumbral regions make their visual delineation difficult. We hypothesized that computational analysis of MRI data provides a more accurate assessment of core and penumbral tissue evolution in HII/AIS. We used two neonatal rat-pup models of HII/AIS (unilateral and global hypoxic-ischemia) and clinical data sets from neonates with AIS to test our noninvasive, automated computational approach, Hierarchical Region Splitting (HRS), to detect and quantify ischemic core-penumbra using only a single MRI modality (T2-or diffusion-weighted imaging, T2WI/DWI). We also validated our approach by comparing core-penumbral images (from HRS) to DPM with immunohistochemical validation of HII tissues. Our translational and clinical data results showed that HRS could accurately and reliably distinguish the ischemic core from penumbra and their spatiotemporal evolution, which may aid in the vetting and execution of effective therapeutic interventions as well as patient selection.

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Failure to complete apoptosis following neonatal hypoxia–ischemia manifests as “continuum” phenotype of cell death and occurs with multiple manifestations of mitochondrial dysfunction in rodent forebrain

Cited by 140 publications

References 44 publications

Combined effect of hypothermia and caspase-2 gene deficiency on neonatal hypoxic–ischemic brain injury

Combined effect of hypothermia and caspase-2 gene deficiency on neonatal hypoxic–ischemic brain injury

Necrostatin Decreases Oxidative Damage, Inflammation, and Injury after Neonatal HI

Automated Core–Penumbra Quantification in Neonatal Ischemic Brain Injury

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