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Neuroprotective effect of dexmedetomidine on hyperoxia-induced toxicity in the neonatal rat brain.

ABSTRACT: Dexmedetomidine is a highly selective agonist of ?2-receptors with sedative, anxiolytic, analgesic, and anesthetic properties. Neuroprotective effects of dexmedetomidine have been reported in various brain injury models. In the present study, we investigated the effects of dexmedetomidine on neurodegeneration, oxidative stress markers, and inflammation following the induction of hyperoxia in neonatal rats. Six-day-old Wistar rats received different concentrations of dexmedetomidine (1, 5, or 10?µg/kg bodyweight) and were exposed to 80% oxygen for 24?h. Sex-matched littermates kept in room air and injected with normal saline or dexmedetomidine served as controls. Dexmedetomidine pretreatment significantly reduced hyperoxia-induced neurodegeneration in different brain regions of the neonatal rat. In addition, dexmedetomidine restored the reduced/oxidized glutathione ratio and attenuated the levels of malondialdehyde, a marker of lipid peroxidation, after exposure to high oxygen concentration. Moreover, administration of dexmedetomidine induced downregulation of IL-1? on mRNA and protein level in the developing rat brain. Dexmedetomidine provides protections against toxic oxygen induced neonatal brain injury which is likely associated with oxidative stress signaling and inflammatory cytokines. Our results suggest that dexmedetomidine may have a therapeutic potential since oxygen administration to neonates is sometimes inevitable.

SUBMITTER: Sifringer M

PROVIDER: S-EPMC4310240 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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Neuroprotective effect of dexmedetomidine on hyperoxia-induced toxicity in the neonatal rat brain.

Sifringer Marco M von Haefen Clarissa C Krain Maria M Paeschke Nadine N Bendix Ivo I Bührer Christoph C Spies Claudia D CD Endesfelder Stefanie S

Oxidative medicine and cellular longevity 20150113

Dexmedetomidine is a highly selective agonist of α2-receptors with sedative, anxiolytic, analgesic, and anesthetic properties. Neuroprotective effects of dexmedetomidine have been reported in various brain injury models. In the present study, we investigated the effects of dexmedetomidine on neurodegeneration, oxidative stress markers, and inflammation following the induction of hyperoxia in neonatal rats. Six-day-old Wistar rats received different concentrations of dexmedetomidine (1, 5, or 10 ...[more]

PMID: 25653737

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Project description:BackgroundNeonatal hyperoxic brain injury is caused by exposure to hyperphysiological oxygen content during the period of incomplete development of the oxidative stress defence system, resulting in a large number of reactive oxygen species (ROS) and causing damage to brain tissue. Mitochondrial biogenesis refers to the synthesis of new mitochondria from existing mitochondria, mostly through the PGC-1α/Nrfs/TFAM signalling pathway. Resveratrol (Res), a silencing information regulator 2-related enzyme 1 (Sirt1) agonist, has been shown to upregulate the level of Sirt1 and the expression of peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α). We speculate that Res has a protective effect on hyperoxia-induced brain injury through mitochondrial biogenesis.MethodsSprague-Dawley (SD) pups were randomly divided into the nonhyperoxia (NN) group, the nonhyperoxia with dimethyl sulfoxide (ND) group, the nonhyperoxia with Res (NR) group, the hyperoxia (HN) group, the hyperoxia with dimethyl sulfoxide (HD) group, and the hyperoxia with Res (HR) group within 12 h after birth. The HN, HD, and HR groups were placed in a high-oxygen environment (80‒85%), and the other three groups were placed in the standard atmosphere. The NR and HR groups were given 60 mg/kg Res every day, the ND and HD groups were given the same dose of dimethyl sulfoxide (DMSO) every day, and the NN and HN groups were given the same dose of normal saline every day. On postnatal day (PN) 1, PN7, and PN14, brain samples were acquired for HE staining to assess pathology, TUNEL to detect apoptosis, and real-time quantitative polymerase chain reaction and immunoblotting to detect the expression levels of Sirt1, PGC-1α, nuclear respiratory factor 1 (Nrf1), nuclear respiratory factor 2 (Nrf2) and mitochondrial transcription factor A (TFAM) in brain tissue.ResultsHyperoxia induced brain tissue injury; increased brain tissue apoptosis; inhibited Sirt1, PGC-1α, Nrf1, Nrf2, TFAM mRNA expression in mitochondria; diminished the ND1 copy number and ND4/ND1 ratio; and decreased Sirt1, PGC-1α, Nrf1, Nrf2, and TFAM protein levels in the brain. In contrast, Res reduced brain injury and attenuated brain tissue apoptosis in neonatal pups and increased the levels of the corresponding indices.ConclusionRes has a protective effect on hyperoxia-induced brain injury in neonatal SD pups by upregulating Sirt1 and stimulating the PGC-1α/Nrfs/TFAM signalling pathway for mitochondrial biogenesis.

Project description:BackgroundNeonatal hyperoxia exposure is associated with brain injury and poor neurodevelopment outcomes in preterm infants. Our previous studies in neonatal rodent models have shown that hyperoxia stimulates the brain's inflammasome pathway, leading to the activation of gasdermin D (GSDMD), a key executor of pyroptotic inflammatory cell death. Moreover, we found pharmacological inhibition of caspase-1, which blocks GSDMD activation, attenuates hyperoxia-induced brain injury in neonatal mice. We hypothesized that GSDMD plays a pathogenic role in hyperoxia-induced neonatal brain injury and that GSDMD gene knockout (KO) will alleviate hyperoxia-induced brain injury.MethodsNewborn GSDMD knockout mice and their wildtype (WT) littermates were randomized within 24 h after birth to be exposed to room air or hyperoxia (85% O2) from postnatal days 1 to 14. Hippocampal brain inflammatory injury was assessed in brain sections by immunohistology for allograft inflammatory factor 1 (AIF1) and CD68, markers of microglial activation. Cell proliferation was evaluated by Ki-67 staining, and cell death was determined by TUNEL assay. RNA sequencing of the hippocampus was performed to identify the transcriptional effects of hyperoxia and GSDMD-KO, and qRT-PCR was performed to confirm some of the significantly regulated genes.ResultsHyperoxia-exposed WT mice had increased microglia consistent with activation, which was associated with decreased cell proliferation and increased cell death in the hippocampal area. Conversely, hyperoxia-exposed GSDMD-KO mice exhibited considerable resistance to hyperoxia as O2 exposure did not increase AIF1 + , CD68 + , or TUNEL + cell numbers or decrease cell proliferation. Hyperoxia exposure differentially regulated 258 genes in WT and only 16 in GSDMD-KO mice compared to room air-exposed WT and GSDMD-KO, respectively. Gene set enrichment analysis showed that in the WT brain, hyperoxia differentially regulated genes associated with neuronal and vascular development and differentiation, axonogenesis, glial cell differentiation, hypoxia-induced factor 1 pathway, and neuronal growth factor pathways. These changes were prevented by GSDMD-KO.ConclusionsGSDMD-KO alleviates hyperoxia-induced inflammatory injury, cell survival and death, and alterations of transcriptional gene expression of pathways involved in neuronal growth, development, and differentiation in the hippocampus of neonatal mice. This suggests that GSDMD plays a pathogenic role in preterm brain injury, and targeting GSDMD may be beneficial in preventing and treating brain injury and poor neurodevelopmental outcomes in preterm infants.

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Neuroprotective effect of dexmedetomidine on hyperoxia-induced toxicity in the neonatal rat brain.

Publications

Neuroprotective effect of dexmedetomidine on hyperoxia-induced toxicity in the neonatal rat brain.

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