| 1. |
- Kichev, A., et al.
(författare)
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TWEAK Receptor Deficiency Has Opposite Effects on Female and Male Mice Subjected to Neonatal Hypoxia-Ischemia
- 2018
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Ingår i: Frontiers in Neurology. - : Frontiers Media SA. - 1664-2295. ; 9
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Tidskriftsartikel (refereegranskat)abstract
- Tumor necrosis factor (TNF)-like weak inducer of apoptosis (TWEAK) is a multifunctional cytokine member of the TNF family. TWEAK binds to its only known receptor, Fn14, enabling it to activate downstream signaling processes in response to tissue injury. The aim of this study was to investigate the role of TWEAK signaling in neonatal hypoxia-ischemia (HI). We found that after neonatal HI, both TWEAK and Fn14 expression were increased to a greater extent in male compared with female mice. To assess the role of TWEAK signaling after HI, the size of the injury was measured in neonatal mice genetically deficient in Fn14 and compared with their wild-type and heterozygote littermates. A significant sex difference in the Fn14 knockout (KO) animals was observed. Fn14 gene KO was beneficial in females; conversely, reducing Fn14 expression exacerbated the brain injury in male mice. Our findings indicate that the TWEAK/Fn14 pathway is critical for development of hypoxic-ischemic brain injury in immature animals. However, as the responses are different in males and females, clinical implementation depends on development of sex-specific therapies.
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| 2. |
- Thornton, C., et al.
(författare)
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Oxidative stress and endoplasmic reticulum (ER) stress in the development of neonatal hypoxic-ischaemic brain injury
- 2017
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Ingår i: Biochemical Society Transactions. - : Portland Press Ltd.. - 0300-5127 .- 1470-8752. ; 45:5, s. 1067-1076
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Forskningsöversikt (refereegranskat)abstract
- Birth asphyxia in term neonates affects 1-2/1000 live births and results in the development of hypoxic-ischaemic encephalopathy with devastating life-long consequences. The majority of neuronal cell death occurs with a delay, providing the potential of a treatment window within which to act. Currently, treatment options are limited to therapeutic hypothermia which is not universally successful. To identify new interventions, we need to understand the molecular mechanisms underlying the injury. Here, we provide an overview of the contribution of both oxidative stress and endoplasmic reticulum stress in the development of neonatal brain injury and identify current preclinical therapeutic strategies.
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| 3. |
- Kichev, A., et al.
(författare)
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Implicating Receptor Activator of NF-kappa B (RANK)/RANK Ligand Signalling in Microglial Responses to Toll-Like Receptor Stimuli
- 2017
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Ingår i: Developmental Neuroscience. - : S. Karger AG. - 0378-5866 .- 1421-9859. ; 39:1-4, s. 192-206
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Tidskriftsartikel (refereegranskat)abstract
- Inflammation in the perinatal brain caused by maternal or intrauterine fetal infection is now well established as an important contributor to the development of perinatal brain injury. Exposure to inflammatory products can impair perinatal brain development and act as a risk factor for neurological dysfunction, cognitive disorders, cerebral palsy, or preterm birth. Pre-exposure to inflammation significantly exacerbates brain injury caused by hypoxic/ischaemic insult. Tumour necrosis factor (TNF) is a family of cytokines largely involved in inflammation signalling. In our previous study, we identified the importance of TNF-related apoptosis-inducing ligand (TRAIL) signalling in the development of perinatal brain injury. We observed a significant increase in the expression levels of a soluble decoy receptor for TRAIL, osteoprotegerin (OPG). Besides TRAIL, OPG is able to bind the receptor activator of the NF-kappa B (RANK) ligand (RANKL) and inhibit its signalling. The function of the RANK/RANKL/OPG system in the brain has not come under much scrutiny. The aim of this research study was to elucidate the role of RANK, RANKL, and OPG in microglial responses to the pro-inflammatory stimuli lipopolysaccharide (LPS) and polyinosinic-polycytidylic acid (Poly I: C). Here, we show that RANK signalling is important for regulating the activation of the BV2 microglial cell line. We found that LPS treatment causes a significant decrease in the expression of RANK in the BV2 cell line while significantly increasing the expression of OPG, Toll-like receptor (TLR) 3, and the adaptor proteins MyD88 and TRIF. We found that pretreatment of BV2 cells with RANKL for 24 h before the LPS or Poly I: C exposure decreases the expression of inflammatory markers such as inducible nitric oxide synthase and cyclooxygenase. This is accompanied by a decreased expression of the TLR adaptor proteins MyD88 and TRIF, which we observed after RANKL treatment. Similar results were obtained in our experiments with primary mouse microglia. Using recently developed CRISPR/Cas9 technology, we generated a BV2 cell line lacking RANK (RANK(-/-) BV2). We showed that most effects of RANKL pretreatment were abolished, thereby proving the specificity of this effect. Taken together, these findings suggest that RANK signalling is important for modulating the inflammatory activation of microglial cells to a moderate level, and that RANK attenuates TLR3/TLR4 signalling. (C) 2017 The Author(s) Published by S. Karger AG, Basel
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| 4. |
- Kichev, Anton, et al.
(författare)
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TNF-related apoptosis-inducing ligand (TRAIL) signaling and cell death in the immature central nervous system after hypoxia-ischemia and inflammation.
- 2014
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Ingår i: The Journal of biological chemistry. - 1083-351X. ; 289:13, s. 9430-39
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Tidskriftsartikel (refereegranskat)abstract
- Tumor Necrosis Factor Related Apoptosis-Inducing Ligand (TRAIL) is a member of the TNF family. The interaction of TRAIL with death receptor 4 (DR4) and DR5 can trigger apoptotic cell death. The aim of this study was to investigate the role of TRAIL signaling in neonatal hypoxia-ischemia (HI). Using a neonatal mouse model of HI, mRNA and protein expression of TRAIL, DR5 and the TRAIL decoy receptors osteoprotegerin (OPG), mDcTRAILR1 and mDcTRAILR2 were determined. In vitro, mRNA expression of these genes was measured in primary neurons and oligodendrocyte progenitor cells (OPCs) after inflammatory cytokine (TNF-α/IFN-γ) treatment and/or oxygen and glucose deprivation (OGD). The toxicity of these various paradigms was also measured. The expression of TRAIL, DR5, OPG and mDcTRAILR2 was significantly increased after HI. In vitro, inflammatory cytokines and OGD treatment significantly induced mRNAs for TRAIL, DR5, OPG and mDcTRAILR2 in primary neurons, and of TRAIL and OPG in OPCs. TRAIL protein was expressed primarily in microglia and astroglia whereas DR5 co-localized with neurons and OPCs in vivo. OGD enhanced TNF-α/IFN-γ toxicity in both neuronal and OPC cultures. Recombinant TRAIL exerted toxicity alone or in combination with OGD and TNF-α/IFN-γ in primary neurons but not in OPC cultures. The marked increases in the expression of TRAIL and its receptors after cytokine exposure and OGD in primary neurons and OPCs were similar to those found in our animal model of neonatal HI. The toxicity of TRAIL in primary neurons suggests that TRAIL signaling participates in neonatal brain injury after inflammation and HI.
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| 5. |
- Rousset, C. I., et al.
(författare)
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A dual role for AMP-activated protein kinase (AMPK) during neonatal hypoxic-ischaemic brain injury in mice
- 2015
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Ingår i: Journal of Neurochemistry. - : Wiley. - 0022-3042. ; 133:2, s. 242-252
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Tidskriftsartikel (refereegranskat)abstract
- Perinatal hypoxic-ischaemic encephalopathy (HIE) occurs in 1-2 in every 1000 term infants and the devastating consequences range from cerebral palsy, epilepsy and neurological deficit to death. Cellular damage post insult occurs after a delay and is mediated by a secondary neural energy failure. AMP-activated protein kinase (AMPK) is a sensor of cellular stress resulting from ATP depletion and/or calcium dysregulation, hallmarks of the neuronal cell death observed after HIE. AMPK activation has been implicated in the models of adult ischaemic injury but, as yet, there have been no studies defining its role in neonatal asphyxia. Here, we find that in anin vivo model of neonatal hypoxia-ischaemic and in oxygen/glucose deprivation in neurons, there is pathological activationof the calcium/calmodulin-dependent protein kinase kinase (CaMKK)-AMPK1 signalling pathway. Pharmacological inhibition of AMPK during the insult promotes neuronal survival but, conversely, inhibiting AMPK activity prior to the insult sensitizes neurons, exacerbating cell death. Our data have pathological relevance for neonatal HIE as prior sensitization such as exposure to bacterial infection (reported to reduce AMPK activity) produces a significant increase in injury.
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| 6. |
- Thornton, Claire, et al.
(författare)
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Molecular mechanisms of neonatal brain injury.
- 2012
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Ingår i: Neurology research international. - : Hindawi Limited. - 2090-1860 .- 2090-1852. ; 2012
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Tidskriftsartikel (refereegranskat)abstract
- Fetal/neonatal brain injury is an important cause of neurological disability. Hypoxia-ischemia and excitotoxicity are considered important insults, and, in spite of their acute nature, brain injury develops over a protracted time period during the primary, secondary, and tertiary phases. The concept that most of the injury develops with a delay after the insult makes it possible to provide effective neuroprotective treatment after the insult. Indeed, hypothermia applied within 6 hours after birth in neonatal encephalopathy reduces neurological disability in clinical trials. In order to develop the next generation of treatment, we need to know more about the pathophysiological mechanism during the secondary and tertiary phases of injury. We review some of the critical molecular events related to mitochondrial dysfunction and apoptosis during the secondary phase and report some recent evidence that intervention may be feasible also days-weeks after the insult.
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