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

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. 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 female newborn piglets were randomized to: (i) no intervention (n = 8); (ii) RIPostC - with four, 10-min cycles of bilateral lower limb ischemia/reperfusion immediately after HI (n = 8). RIPostC reduced the hypoxic-ischemic-induced increase in white matter proton MRS lactate/N acetyl aspartate (p = 0.005) and increased whole brain phosphorus-31 MRS ATP (p = 0.039) over the 48 h after HI. Cell death was reduced with RIPostC in the periventricular white matter (p = 0.03), internal capsule (p = 0.002) and corpus callosum (p = 0.021); there was reduced microglial activation in corpus callosum (p = 0.001) and more surviving oligodendrocytes in corpus callosum (p = 0.029) and periventricular white matter (p = 0.001). Changes in gene expression were detected in the white matter at 48 h, including KATP channel and endothelin A receptor. Immediate RIPostC is a potentially safe and promising brain protective therapy for babies with NE with protection in white but not grey matter.

SUBMITTER: Ezzati M

PROVIDER: S-EPMC4976661 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Introduction: Hypoxic ischemic encephalopathy (HIE) is a major cause of death and disability in children worldwide. Apart from supportive care, the only established treatment for HIE is therapeutic hypothermia (TH). As TH is only partly neuroprotective, there is a need for additional therapies. Intermittent periods of limb ischemia, called remote ischemic postconditioning (RIPC), have been shown to be neuroprotective after HIE in rats and piglets. However, it is unknown whether RIPC adds to the effect of TH. We tested the neuroprotective effect of RIPC with TH compared to TH alone using magnetic resonance imaging and spectroscopy (MRI/MRS) in a piglet HIE model. Methods: Thirty-two male and female piglets were subjected to 45-min global hypoxia-ischemia (HI). Twenty-six animals were randomized to TH or RIPC plus TH; six animals received supportive care only. TH was induced through whole-body cooling. RIPC was induced 1 h after HI by four cycles of 5 min of ischemia and 5 min of reperfusion in both hind limbs. Primary outcome was Lac/NAA ratio at 24 h measured by MRS. Secondary outcomes were NAA/Cr, diffusion-weighted imaging (DWI), arterial spin labeling, aEGG score, and blood oxygen dependent (BOLD) signal measured by MRI/MRS at 6, 12, and 24 h after the hypoxic-ischemic insult. Results: All groups were subjected to a comparable but mild insult. No difference was found between the two intervention groups in Lac/NAA ratio, NAA/Cr ratio, DWI, arterial spin labeling, or BOLD signal. NAA/Cr ratio at 24 h was higher in the two intervention groups compared to supportive care only. There was no difference in aEEG score between the three groups. Conclusion: Treatment with RIPC resulted in no additional neuroprotection when combined with TH. However, insult severity was mild and only evaluated at 24 h after HI with a short MRS echo time. In future studies more subtle neurological effects may be detected with increased MRS echo time and post mortem investigations, such as brain histology. Thus, the possible neuroprotective effect of RIPC needs further evaluation.

Project description:Background Remote limb ischemic postconditioning (RLIPoC) has been demonstrated to protect against ischemic stroke. However, the underlying mechanisms of RLIPoC mediating cross-organ protection remain to be fully elucidated. Methods and Results Ischemic stroke was induced by middle cerebral artery occlusion for 60 minutes. RLIPoC was performed with 3 cycles of 10-minute ischemia followed by 10-minute reperfusion of the bilateral femoral arteries immediately after middle cerebral artery reperfusion. The percentage of regulatory T cells (Tregs) in the spleen, blood, and brain was detected using flow cytometry, and the number of Tregs in the ischemic hemisphere was counted using transgenic mice with an enhanced green fluorescent protein-tagged Foxp3. Furthermore, the metabolic status was monitored dynamically using a multispectral optical imaging system. The Tregs were conditionally depleted in the depletion of Treg transgenic mice after the injection of the diphtheria toxin. The inflammatory response and neuronal apoptosis were investigated using immunofluorescent staining. Infarct volume and neurological deficits were evaluated using magnetic resonance imaging and the modified neurological severity score, respectively. The results showed that RLIPoC substantially reduced infarct volume, improved neurological function, and significantly increased Tregs in the spleen, blood, and ischemic hemisphere after middle cerebral artery occlusion. RLIPoC was followed by subsequent alteration in metabolites, such as flavin adenine dinucleotide and nicotinamide adenine dinucleotide hydrate, both in RLIPoC-conducted local tissues and circulating blood. Furthermore, nicotinamide adenine dinucleotide hydrate can mimic RLIPoC in increasing Tregs. Conversely, the depletion of Tregs using depletion of Treg mice compromised the neuroprotective effects conferred by RLIPoC. Conclusions RLIPoC protects against ischemic brain injury, at least in part by activating and maintaining the Tregs through the nicotinamide adenine dinucleotide/nicotinamide adenine dinucleotide hydrate pathway.

Project description:BackgroundBlood flow restoration is a definitive therapy for salvaging the myocardium following ischemic injury. Nevertheless, the sudden restoration of blood flow to the ischemic myocardium can induce ischemia-reperfusion injury (IRI).ResultsHerein, we investigated the cardioprotective effect of remote ischemic postconditioning (RPostC) through our in vivo rat model of myocardial IRI. The study included three groups: the control group, the IRI group, and the IRI + RPostC group. Ischemia-reperfusion treatment led to an increase in the myocardial infarction area, which was inhibited by RPostC. In contrast to that in the control group, the myocardial apoptosis level was enhanced in the IRI group, whereas RPostC treatment decreased IRI-induced cellular apoptosis. Affymetrix Rat Gene 2.0 ST chip data identified a total of 265 upregulated genes and 267 downregulated genes between the IRI and IRI + RPostC groups. A group of differentially expressed noncoding RNAs (ncRNAs), such as MTA_TC0600002772.mm, MTA_TC1300002394.mm, U7 small nuclear RNA (Rnu7) and RGD7543256_1, were identified. Gene Ontology (GO) enrichment analysis indicated that the positive regulation of some molecular functions, such as GTPase activity, GTP binding, cyclic-nucleotide phosphodiesterase activity and cytokine activity, may contribute to the cardioprotective role of RPostC. Moreover, pathway enrichment analysis using the Kyoto Encyclopedia of Genes and Genomes (KEGG) suggested the potential implication of the TNF signaling pathway and Toll-like receptor signaling pathway. Global signal transduction network analysis, co-expression network analysis and quantitative real-time polymerase chain reaction analysis further identified several core genes, including Pdgfra, Stat1, Lifr and Stfa3.ConclusionRemote ischemic postconditioning treatment can decrease IRI-mediated myocardial apoptosis by regulating multiple processes and pathways, such as GTPase activity, cytokine activity, and the TNF and Toll-like receptor signaling pathways. The potential role of the above ncRNAs and core genes in IRI-induced cardiac damage merits further study as well.

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

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