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PML regulates neuroprotective innate immunity and neuroblast commitment in a hypoxic-ischemic encephalopathy model.

ABSTRACT: Regulation of innate immune responses and activation of tissue regenerative processes are key elements in the pathophysiology of brain injuries. The promyelocytic leukemia (PML) gene was originally identified on a breakpoint of chromosomal translocation t(15;17) associated with acute PML. We have studied the role of PML protein during acute and regenerative phases after hypoxia-ischemia (HI) in brains of neonatal mice. We found that PML prevents tissue loss and apoptotic cell death selectively in subcortical regions of the brain at early stages after damage. In accordance with this, we revealed that PML is important for microglia activation and production of key inflammatory cytokines such as IL1?, IL1?, IL1RN, CXCL10, CCL12 and TNF?. During the regenerative phase, PML-depleted mice were found to have impaired transformation of transit-amplifying precursors into migratory progenitors. This was accompanied by increased ratios of symmetric versus asymmetric neural progenitor cell divisions during tissue repair and a specific defect in tissue restoration within the striatum 42 days after HI. The data demonstrate a dual role of PML in protection and recovery after brain injury.

SUBMITTER: Palibrk V

PROVIDER: S-EPMC4973360 | biostudies-literature | 2016 Jul

REPOSITORIES: biostudies-literature

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PML regulates neuroprotective innate immunity and neuroblast commitment in a hypoxic-ischemic encephalopathy model.

Palibrk Vuk V Suganthan Rajikala R Scheffler Katja K Wang Wei W Bjørås Magnar M Bøe Stig Ove SO

Cell death & disease 20160728 7

Regulation of innate immune responses and activation of tissue regenerative processes are key elements in the pathophysiology of brain injuries. The promyelocytic leukemia (PML) gene was originally identified on a breakpoint of chromosomal translocation t(15;17) associated with acute PML. We have studied the role of PML protein during acute and regenerative phases after hypoxia-ischemia (HI) in brains of neonatal mice. We found that PML prevents tissue loss and apoptotic cell death selectively i ...[more]

PMID: 27468695

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Project description:Context: Several interventions are available for the management of hypoxic ischemic encephalopathy (HIE), but no studies have compared their relative efficacy in a single analysis. This study aims to compare and determine the effectiveness of available interventions for HIE using direct and indirect data. Methods: Large randomized trials were identified from PubMed, EMBASE, CINAHL Plus, AMED, and Cochrane Library of Clinical Trials database from inception until June 30, 2018. Two independent reviewers extracted study data and performed quality assessment. Direct and network meta-analysis of randomized controlled trials was performed to obtained pooled results comparing the effectiveness of different therapies used in HIE on mortality, neurodevelopmental delay at 18 months, as well as adverse events. Their probability of having the highest efficacy and safety was estimated and ranked. The certainty of evidence for the primary outcomes of mortality and mortality or neurodevelopmental delay at 18 months was evaluated using GRADE criteria. Results: Fifteen studies comparing five interventions were included in the network meta-analysis. Whole body cooling [Odds ratio: 0.62 (95% credible interval: 0.46-0.83); 8 trials, high certainty of evidence] was the most effective treatment in reducing the risk of mortality, followed by selective head cooling (0.73; 0.48-1.11; 2 trials, moderate certainty of evidence) and use of magnesium sulfate (0.79; 0.20-3.06; 2 trials, low certainty of evidence). Whole body hypothermia (0.48; 0.33-0.71; 5 trials), selective head hypothermia (0.54; 0.32-0.89; 2 trials), and erythropoietin (0.36; 0.19-0.66; 2 trials) were more effective for reducing the risk of mortality and neurodevelopmental delay at 18 months (moderate to high certainty). Among neonates treated for HIE, the use of erythropoietin (0.36; 0.18-0.74, 2 trials) and whole body hypothermia (0.61; 0.45-0.83; 7 trials) were associated with lower rates of cerebral palsy. Similarly, there were lower rates of seizures among neonates treated with erythropoietin (0.35; 0.13-0.94; 1 trial) and whole body hypothermia (0.64; 0.46-0.87, 7 trials). Conclusion: The findings support current guidelines using therapeutic hypothermia in neonates with HIE. However, more trials are needed to determine the role of adjuvant therapy to hypothermia in reducing the risk of mortality and/or neurodevelopmental delay.

Dataset Information

PML regulates neuroprotective innate immunity and neuroblast commitment in a hypoxic-ischemic encephalopathy model.

Publications

PML regulates neuroprotective innate immunity and neuroblast commitment in a hypoxic-ischemic encephalopathy model.

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