Unknown,Transcriptomics,Genomics,Proteomics

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Gene expression changes in the periventricular white matter of neonatal piglets at a defined 48h time point following a hypoxic-ischemic insult: a comparison of piglets left untreated and those treated with a remote post-conditioning stimulus applied to the hind leg immediately after the insult.

ABSTRACT: Remote ischemic postconditioning (RIPostC) is a promising therapeutic intervention whereby brief episodes of ischemia/reperfusion of one organ (limb) mitigate damage in another organ (brain) that has experienced severe hypoxia-ischemia. 16 Large White newborn female piglets were exposed to a tightly controlled hypoxic-ischemic insult using magnetic resonance spectroscopy (MRS) biomarkers. After hypoxia-ischemia (HI), piglets were randomized to: (i) no intervention (nâ=â8); (ii) RIPostC â with four, 10-min cycles of bilateral lower limb ischemia/reperfusion immediately after HI (nâ=â8). Piglets in the remote post-conditioned group exhibited a reduction in white matter proton MRS lactate/N acetyl aspartate and increased whole brain phosphorus-31 MRS ATP over the 48âh after hypoxia-ischemia. Cell death (apoptosis) was reduced with RIPostC in the periventricular white matter, internal capsule and corpus callosum. There was also reduced microglial activation in corpus callosum and more surviving oligodendrocytes in corpus callosum and periventricular white matter. Our results demonstrate changes in the expression of 74 genes in the periventricular white matter 63 were down regulated and 11 were upregulated, that accompany the reductions in cell death and microglial activation seen following a remote post conditioning stimulus at a single 48h time point. (significance was calculated at p<0.05, one way ANOVA, Mann-Whitney unpaired, noe were found to be significant following a Benjamini-Hochberg FDR multipe testing correction). Many of these genes are thought to be important for the mediation of the neuroprotective effects of post-conditioning which suggests its genomic effects may persist for 48h. A full description of this work can be accessed at doi: 10.1177/0271678X15608862.

ORGANISM(S): Sus scrofa

SUBMITTER: Dr Mojgan Ezzati

PROVIDER: E-MTAB-5125 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

Immediate remote ischemic postconditioning after hypoxia ischemia in piglets protects cerebral white matter but not grey matter.

Ezzati Mojgan M Bainbridge Alan A Broad Kevin D KD Kawano Go G Oliver-Taylor Aaron A Rocha-Ferreira Eridan E Alonso-Alconada Daniel D Fierens Igor I Rostami Jamshid J Jane Hassell K K Tachtsidis Ilias I Gressens Pierre P Hristova Mariya M Bennett Kate K Lebon Sophie S Fleiss Bobbi B Yellon Derek D Hausenloy Derek J DJ Golay Xavier X Robertson Nicola J NJ

Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism 20151008 8

Remote ischemic postconditioning (RIPostC) is a promising therapeutic intervention whereby brief episodes of ischemia/reperfusion of one organ (limb) mitigate damage in another organ (brain) that has experienced severe hypoxia-ischemia. Our aim was to assess whether RIPostC is protective following cerebral hypoxia-ischemia in a piglet model of neonatal encephalopathy (NE) using magnetic resonance spectroscopy (MRS) biomarkers and immunohistochemistry. After hypoxia-ischemia (HI), 16 Large White ...[more]

PMID: 26661194

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Project description:Vascular cognitive impairment and dementia (VCID) is the second most common form of dementia after Alzheimer’s disease (AD). Currently, the mechanistic insights into the evolution and progression of VCID remain elusive. White matter change represents an invariant feature. Compelling clinical neuroimaging and pathological evidence suggest a link between white matter changes and neurodegeneration. Our prior study detected hypoperfused lesions in mice with partial deficiency of endothelial nitric oxide (eNOS) at very young age, precisely matching to those hypoperfused areas identified in preclinical AD patients. White matter tracts are particularly susceptible to the vascular damage induced by chronic hypoperfusion. Using immunohistochemistry, we detected severe demyelination in the middle aged eNOS-deficient mice. The demyelinated areas were confined to cortical and subcortical areas including the corpus callosum and hippocampus. The intensity of demyelination correlated with behavioral deficits of gait and associative recognition memory performances. By Evans blue angiography, we detected blood-brain barrier (BBB) leakage as another early pathological change affecting frontal and parietal cortex in eNOS-deficient mic. Sodium nitrate fortified drinking water provided to young and middle aged eNOS-deficient mice completely prevented non-perfusion, BBB leakage, and white matter pathology, indicating that impaired endothelium-derived NO signaling may have caused these pathological events. Furthermore, genome-wide transcriptomic analysis revealed altered gene clusters most related to mitochondrial respiratory pathways selectively in the white matter of young eNOS-deficient mice. Using eNOS-deficient mice, we identified BBB breakdown and hypoperfusion as the two earliest pathological events, resulting from insufficient vascular NO signaling. We speculate that the compromised BBB and mild chronic hypoperfusion trigger vascular damage, along with oxidative stress and astrogliosis, accounting for the white matter pathological changes in the eNOS-deficient mouse model. We conclude that eNOS-deficient mice represent an ideal spontaneous evolving model for studying the earliest events leading to spontaneous white matter changes, which will be instrumental to future therapeutic testing of drug candidates and for targeting novel/specific vascular mechanisms contributing to VCID and AD.

Dataset Information

Gene expression changes in the periventricular white matter of neonatal piglets at a defined 48h time point following a hypoxic-ischemic insult: a comparison of piglets left untreated and those treated with a remote post-conditioning stimulus applied to the hind leg immediately after the insult.

Publications

Immediate remote ischemic postconditioning after hypoxia ischemia in piglets protects cerebral white matter but not grey matter.

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