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Cited by 130Neonatal and fetal brain pathologyNeuroinflammation and Neurodegeneration MechanismsInflammatory mediators and NSAID effects

Reactive astrocyte COX2-PGE2 production inhibits oligodendrocyte maturation in neonatal white matter injury

Open access
Shiow, Lawrence R., Favrais, Geraldine, Schirmer, Lucas, Schang, Anne‐Laure, Cipriani, Sara, Andres, Christian, Wright, Jaclyn N., Nobuta, Hiroko +3 more·2017·Glia
DOI 10.1002/glia.23212PMC PMC5753598
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Abstract

Inflammation is a major risk factor for neonatal white matter injury (NWMI), which is associated with later development of cerebral palsy. Although recent studies have demonstrated maturation arrest of oligodendrocyte progenitor cells (OPCs) in NWMI, the identity of inflammatory mediators with direct effects on OPCs has been unclear. Here, we investigated downstream effects of pro‐inflammatory IL‐1β to induce cyclooxygenase‐2 (COX2) and prostaglandin E2 (PGE2) production in white matter. First, we assessed COX2 expression in human fetal brain and term neonatal brain affected by hypoxic‐ischemic encephalopathy (HIE). In the developing human brain, COX2 was expressed in radial glia, microglia, and endothelial cells. In human term neonatal HIE cases with subcortical WMI, COX2 was strongly induced in reactive astrocytes with “A2” reactivity. Next, we show that OPCs express the EP1 receptor for PGE2, and PGE2 acts directly on OPCs to block maturation in vitro. Pharmacologic blockade with EP1‐specific inhibitors (ONO‐8711, SC‐51089), or genetic deficiency of EP1 attenuated effects of PGE2. In an IL‐1β‐induced model of NWMI, astrocytes also exhibit “A2” reactivity and induce COX2. Furthermore, in vivo inhibition of COX2 with Nimesulide rescues hypomyelination and behavioral impairment. These findings suggest that neonatal white matter astrocytes can develop “A2” reactivity that contributes to OPC maturation arrest in NWMI through induction of COX2‐PGE2 signaling, a pathway that can be targeted for neonatal neuroprotection.

AI snapshot

Written from the paper’s full text.

TL;DR

Reactive astrocytes in neonatal white matter injury develop an “A2” phenotype and induce COX2, producing PGE2 that acts directly on oligodendrocyte progenitor cells through EP1 to block maturation. In an IL-1β mouse model, COX2 inhibition with Nimesulide rescued hypomyelination and behavioral impairment.

Key findings

  • In human fetal brain (27-, 30-, and 31-week gestational age cases), COX2 was expressed in Iba1+ microglia, Nestin+ radial glia, and CD34+ endothelial cells; in term neonatal hypoxic-ischemic encephalopathy with subcortical white matter injury, COX2 was strongly induced in reactive GFAP+ astrocytes co-expressing the “A2” marker S100A10.
  • Systemic IL-1β in mice increased COX2 transcript in isolated CD11b+ microglia and GLAST+ astrocytes, and astrocytes showed increased “A2” markers S100a10 and Emp1 without induction of “A1” markers Fbln5, Amigo2, or Serping1.
  • PGE2 directly and dose-dependently suppressed T3-induced MBP expression in mouse and rat OPC cultures, maintained immature Nkx2.2 expression, and had no effect on Olig2+ cell numbers, BrdU incorporation, phospho-histone 3, or LDH release.
  • EP1 mediated this effect: OPCs expressed EP1, EP1 inhibitors ONO-8711 and SC-51089 reversed PGE2 effects, and EP1−/− OPCs were resistant to PGE2; in vivo, Nimesulide prevented IL-1β-induced NG2+ cell increases at P5 and MBP density decreases at P30, and preserved performance in novel object recognition and object location memory tests at P29–P30.

Methods

  • Human post-mortem fetal brain tissue from 27-, 30-, and 31-week gestational age cases and term HIE/control cases was analyzed by immunohistochemistry/immunofluorescence for COX2, GFAP, S100A10, Iba1, Nestin, and CD34.
  • Mouse and rat OPC cultures, mixed glial cultures, and EP1−/− mice were used with PGE2, IL-1β, ONO-8711, SC-51089, and Nimesulide; in vivo, mice received intraperitoneal IL-1β at 10 μg/kg/injection from P1–P5 and Nimesulide at 1 mg/kg/injection, with qPCR, ELISA, Western blot, histology, and behavioral testing.
  • Analyses used unpaired two-tailed t-tests or Mann-Whitney U tests for two groups and one-way ANOVA for three or more groups.

Limitations

  • The paper states that the IL-1β-induced white matter model was conducted in male pups only, so sex differences were not assessed.
  • The paper states that control human cases included infants with congenital diaphragmatic hernia, which may result in hypoxemia, though controls did not show astrogliosis or macrophage infiltration.
  • The paper states that downstream EP1 signaling in OPCs remains unidentified; no evidence was found for Wnt/β-catenin, HIF1α, p38MAPK, JNK, p65NFκB, IκBα, STAT3, or Akt changes. Evident from the text: human data are largely descriptive/correlative, and the causal therapeutic evidence comes from rodent and in vitro models.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1002/glia.23212

Cites

71 of 71 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 48 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    In term neonatal HIE with subcortical WMI, reactive astrocytes with A2 reactivity show strong COX2 induction.

    “In human term neonatal hypoxic-ischemic encephalopathy cases with subcortical WMI, COX2 was strongly induced in reactive astrocytes with “A2” reactivity.”
    • Also stated in: § COX2 protein is induced by human reactive astrocytes in neonatal white matter · boosted
      “These findings show that COX2 is strongly induced in human HIE white matter within reactive astrocytes of an “A2”-associated phenotype”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The HIE cases with subcortical WMI represent human neonatal white matter injury.
  • Findingown data

    In vitro, PGE2 directly prevents OPC maturation.

    “PGE2 acts directly on OPCs to block maturation in vitro.”
    Quote in the paperSubstantial claim
  • Findingown data

    IL-1β stimulation of mixed glial cultures increased COX2 protein.

    “IL-1β stimulation of mixed glial cultures resulted in elevated COX2 protein consistent with previously published work that COX2 could be induced by astrocytes or microglia (Katsuura et al., 1989; Molina-Holgado et al., 2000).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Katsuura et al., 1989

      Not checked in the free run.

    • cites Molina-Holgado et al., 2000

      Not checked in the free run.

  • Findingown data

    In HIE cases, GFAP+ white matter astrocytes strongly co-express the A2 marker S100A10.

    “we also looked for expression of the “A2” associated marker, S100A10, and found strong co-expression within GFAP+ white matter astrocytes in HIE cases (Fig. 2 E and F).”
    Quote in the paperSubstantial claim
  • Findingown data

    COX2 protein is present in radial glia, microglia, and endothelial cells of the developing human brain.

    “In the developing human brain, COX2 was expressed in radial glia, microglia, and endothelial cells.”
    • Also stated in: § COX2 protein is expressed in glial cells of the 3rd trimester human fetal brain · hedged
      “In the three cases, IHC staining revealed COX2 expression in Iba1-positive microglia (Fig. 1 A), Nestin-positive putative radial glia (including a subset of immature astrocytes) (Fig. 1 B), and CD34-positive endothelial cells (Fig. 1 C) within the sub-ventricular zone.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: The three human fetal brain samples without overt damage represent normal developing human brain.
  • May combine two claims. 28
  • Classified as probably not a substantial claim. 17

  • May combine two claims.

    Findingown data

    EP1-specific antagonists ONO-8711 and SC-51089, or EP1 genetic loss, reduce PGE2 effects.

    “Pharmacologic blockade with EP1-specific inhibitors (ONO-8711, SC-51089), or genetic deficiency of EP1 attenuated effects of PGE2.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In the IL-1β NWMI model, astrocytes show A2 reactivity and COX2 induction.

    “In an IL-1β-induced model of NWMI, astrocytes also exhibit “A2” reactivity and induce COX2.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    After systemic IL-1β, isolated CD11b+ microglia and GLAST+ astrocytes both show higher COX2 mRNA than controls.

    “both CD11b+ microglia and GLAST+ astrocytes isolated from IL-1β treated animals expressed elevated levels of COX2 transcript compared to controls.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In GLAST+ astrocytes from IL-1β-treated mice, A2 markers S100a10 and Emp1 increase, while A1 markers Fbln5, Amigo2, and Serping1 do not.

    “the expression pattern shows a differential increase the A2-associated markers S100a10 and Emp1 but lack of induction for A1-associated markers (Fbln5, Amigo2, Serping1).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    HIE cases show more GFAP+ astrocytes and higher COX2 expression in those astrocytes than controls.

    “we found that GFAP+ astrocytes exhibited a significant increase in total numbers and COX2 expression.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Total CD45+ cell numbers and their COX2 expression do not differ between HIE and control cases.

    “CD45+ cells were unchanged in total numbers or COX2 expression (Fig. 2 D).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Nimesulide-mediated COX2 inhibition in vivo reverses hypomyelination and behavioral deficits.

    “in vivo inhibition of COX2 with Nimesulide rescues hypomyelination and behavioral impairment.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Nimesulide acts as a selective COX2 inhibitor.

  • May combine two claims.

    Findingown data

    IL-1β-stimulated mixed glial cultures produced PGE2, and this production was inhibited by Nimesulide, a COX2-specific inhibitor.

    “IL-1β-stimulated mixed glial cultures also produced PGE2 and this was inhibited by Nimesulide, which specifically targets COX2 (Supplementary Figure. 1 B).”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Nimesulide specifically inhibits COX2.

  • May combine two claims.

    Findingown data

    When purified OPCs were treated directly with IL-1β, COX2 was not induced and maturation arrest did not occur.

    “In contrast, we found that direct IL-1β treatment of purified OPCs did not induce COX2 or lead to OPC maturation arrest (Supplementary Figure. 1 A and C), consistent with a previous study (Vela, 2002).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Vela, 2002

      Not checked in the free run.

  • May combine two claims.

    Findingown data

    In novel object recognition and object location memory tests at P29 and P30, mice co-treated with IL-1β and Nimesulide performed like controls, while IL-1β alone showed memory deficits.

    “In novel object recognition and object location memory tests performed at P29 and P30, animals co-treated with IL-1β and Nimesulide performed as controls while animals treated with IL-1β alone showed memory deficits (Fig. 6 G).”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Nimesulide specifically inhibits COX2.

  • May combine two claims.

    Findingown data

    OPCs purified from EP1-/- mice were resistant to PGE2 effects, unlike littermate EP1+/- control cells.

    “In contrast to control cells, EP1-/- OPCs were resistant to the effects of PGE2 (Fig. 5 F and G).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    PGE2 blocked OPC maturation, as shown by persistent expression of immature OPC marker Nkx2.2.

    “We confirmed that PGE2 blocked OPC maturation by monitoring persistent expression of immature OPC marker Nk×2.2 (Fig. 4 D).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In a mouse model of inflammation-induced NWMI, a COX2-specific inhibitor preserved myelination and reduced cognitive impairment.

    “In human neonatal white matter pathology, reactive astrocytes with an “A2” phenotype strongly induce COX2, and treatment with a COX2-specific inhibitor is protective in a mouse model of inflammation-induced NWMI with preserved myelination and attenuated cognitive impairment.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    BrdU incorporation and histone-3 phosphorylation did not differ between PGE2 and control treated cells.

    “An assessment of BrdU incorporation (Fig. 4 H) and histone-3 phosphorylation (Fig. 4 I) showed no difference between PGE2 and control treated cells.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    ONO-8711, an EP1-specific inhibitor, reversed PGE2 effects on MBP expression and maintained Nkx2.2 in mouse OPCs.

    “ONO-8711 is an EP1-specific inhibitor (Watanabe et al., 1999) and co-treatment of ONO-8711 reversed effects of PGE2 on MBP expression and maintained Nk×2.2 (Fig. 5 C and D).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Watanabe et al., 1999

      Not checked in the free run.

  • May combine two claims.

    Findingown data

    Following PGE2 exposure, OPCs showed no signs of β-catenin activation or HIF1α stabilization.

    “While PGE2 effects have been associated with interactions with Wnt or HIF1α signaling (Goessling et al., 2009; Ji et al., 2010), we found no evidence of β-catenin activation or HIF1α stabilization in OPCs following PGE2 exposure (Supplementary Figure. 2 A and B).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Goessling et al., 2009

      Not checked in the free run.

    • cites Ji et al., 2010

      Not checked in the free run.

  • May combine two claims.

    Findingown data

    Human neonatal white matter lesions contain reactive astrocytes that express the A2 phenotype and show strong COX2 induction.

    “In human neonatal white matter pathology, reactive astrocytes with an “A2” phenotype strongly induce COX2, and treatment with a COX2-specific inhibitor is protective in a mouse model of inflammation-induced NWMI with preserved myelination and attenuated cognitive impairment.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The human control cases with diaphragmatic hernia did not have gliosis or inflammatory infiltration despite possible milder hypoxia.

  • May combine two claims.

    Findingown data

    At P5, nimesulide blocked the IL-1β-induced rise in NG2+ cells, and at P30 it blocked the loss of MBP staining density in the sensory-motor cortex.

    “Nimesulide prevented the IL-1β-induced increase of NG2 + cells at P5 and the decrease in MBP staining density within the sensory-motor cortex at P30 (Fig. 6 D-F).”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Nimesulide specifically inhibits COX2.

  • May combine two claims.

    Premisecitation

    In NWMI, OPCs remain present but are held in an immature pre-myelinating state.

    “more recent histologic studies using markers of discrete stages of OPC development in NWMI reveal that OPCs are present but arrested in a pre-myelinating and immature state (Billiards et al., 2008; Buser et al., 2012; Verney et al., 2012).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Billiards et al., 2008

      Not checked in the free run.

    • cites Buser et al., 2012

      Not checked in the free run.

    • cites Verney et al., 2012

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Factors induced by reactive astrocytes, including hyaluronic acid, BMP, and endothelin-1, can impair OPC maturation.

    “While factors induced by reactive astrocytes such as hyaluronic acid (Back et al., 2005), BMP (Wang et al., 2011), endothelin-1(Hammond et al., 2014) can impair OPC maturation”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Back et al., 2005

      Not checked in the free run.

    • cites Wang et al., 2011

      Not checked in the free run.

    • cites Hammond et al., 2014

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    EP1 mouse experiments used littermate controls.

    “all experiments involving EP1 mice utilized littermate controls.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Premisecitation

    Mouse transcriptional studies of reactive astrocyte subtypes linked Cox2 induction to the A2 phenotype.

    “In transcriptional assessments of reactive astrocyte subtypes in mouse models, induction of Cox2 was associated with the “A2” phenotype (Zamanian et al., 2012; Liddelow et al., 2017).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Zamanian et al., 2012

      Not checked in the free run.

    • cites Liddelow et al., 2017

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductreasoning

    Only male pups were used in the IL-1β white matter model, so sex differences were not evaluated.

    “Because the IL-1β-induced white matter model was conducted in male pups only, sex differences were not assessed.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductown data

    Mouse OPC cultures were >95% Olig2+, <1% Iba1+, and <4% GFAP+ by IHC.

    “Purified cell preparations were >95% Olig2+, <1% Iba1+ and <4% GFAP+ as assessed by IHC (data not shown).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    PGE2 acts through cell-surface EP receptors.

    “and signals to the EP family of cell surface receptors (Legler et al., 2010).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Legler et al., 2010

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    STAT3-dependent astrocyte reactivity is protective.

    “STAT3-dependent astrocyte reactivity is also protective (Nobuta et al., 2012)”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Nobuta et al., 2012

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    A1-marker-expressing reactive astrocytes occur in several adult human neurodegenerative diseases and are considered neurotoxic.

    “Reactive astrocytes expressing “A1” markers are found in multiple adult human neurodegenerative conditions and are thought to confer neurotoxic effects.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Liddelow et al., 2017

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    Rat OPC cultures were >90% pure at day 4.

    “OPC purity had been assessed > 90% at day 4 (data not shown).”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    MACS fraction purity was checked by qRT-PCR for Gfap, NeuN, Iba1, and Olig2.

    “The purity of fractions was verified using qRT-PCR for glial fibrillary acid protein (Gfap), neuronal nuclear antigen (Rbfox3, NeuN), ionizing calcium binding adapter protein (Aif1, Iba1), and oligodendrocyte differentiation factor 2 (Olig2).”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Premisecitation

    Arachidonic acid is converted to PGE2 by rate-limiting COX enzymes.

    “Prostaglandin E2 (PGE2) is a pro-inflammatory mediator that is derived from arachidonic acid through the rate-limiting cyclooxygenase (COX) enzymes”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Legler et al., 2010

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    The data indicate that in human HIE white matter, A2-like reactive astrocytes strongly induce COX2 and may be a major PGE2 source in NWMI.

    “These findings show that COX2 is strongly induced in human HIE white matter within reactive astrocytes of an “A2”-associated phenotype, and suggests that “A2” reactive astrocytes may be an important source of PGE2 in human NWMI.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    Loss of EP1 did not cause obvious gross brain malformation.

    “EP1 deficiency did not grossly affect brain morphology (data not shown).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Reactive astrocytes can have either protective or deleterious effects.

    “and can have either protective or deleterious effects (Williams et al., 2007; Sofroniew, 2015).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Williams et al., 2007

      Not checked in the free run.

    • cites Sofroniew, 2015

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    A1 and A2 are molecularly defined subtypes of reactive astrocytes.

    “Reactive astrocytes have recently been subtyped as “A1” or “A2” based on distinct molecular markers (Liddelow et al., 2017).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Liddelow et al., 2017

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    0.1% DMSO alone had no effects.

    “0.1% DMSO alone had no effects (data not shown).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    The findings indicate that IL-1β causes astrocytes and microglia, but not OPCs, to generate PGE2 via a COX2-dependent route.

    “Taken together, these findings indicate that IL-1β activates astrocytes and microglia, but not OPCs, to produce PGE2 in a COX2-dependent manner.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Earlier trials of nonselective COX inhibitors reduced severe intraventricular hemorrhage, but those trials lacked power or design to assess NWMI.

    “Previous studies using nonspecific COX inhibitors, such as indomethacin or ibuprofen, to promote patent ductus arteriosus (PDA) closure in preterm infants showed benefit for the prevention of severe intraventricular hemorrhage (Ment et al., 1994; Schmidt et al., 2001) but they were not powered or designed to evaluate NWMI.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Ment et al., 1994 source

      Not checked in the free run.

    • cites Schmidt et al., 2001

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Prior work proposes that A1 and A2 reactive astrocyte subtypes mark neurotoxic and regenerative states, respectively.

    “Reactive astrocytes subtypes “A1” and “A2” (Liddelow et al., 2017) have been suggested to demarcate neurotoxic vs. regenerative forms (Sofroniew, 2015).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Liddelow et al., 2017

      Not checked in the free run.

    • cites Sofroniew, 2015

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    In vitro, PGE2 strongly blocks maturation of mouse and rat OPCs without altering their proliferation or survival.

    “Thus, PGE2 is a potent inhibitor of mouse and rat OPC maturation in vitro, but does not affect OPC proliferation or survival.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    Rather than killing cells, PGE2 may act as a modulator that arrests OPC maturation, a role that fits diffuse NWMI.

    “As such, this role for PGE2 as a modulator rather than a toxic mediator in leading to OPC maturation arrest may be more consistent with today's predominant form of neonatal brain injury with diffuse NWMI.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    The authors propose a model in which inflammation and perinatal insults cause A2 reactive astrocytes to make PGE2, which then directly blocks OPC maturation and myelination.

    “Taken together, our findings support a model (Fig. 7) in which systemic inflammation and perinatal insults can induce “A2” reactive astrocytes to produce PGE2 that directly impairs OPC maturation and myelination.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Inhibition of PGE2 signaling attenuates an in vitro model of excitotoxic OPC death.

    “Inhibition of PGE2 signaling also attenuates an in vitro model of excitotoxic OPC death (Carlson et al., 2015).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Carlson et al., 2015

      Not checked in the free run.

42 of 42

  • The paper relies on this without support.

    The three human fetal brain samples without overt damage represent normal developing human brain.

    “Post-mortem fetal human brain sections were obtained from three cases of 27-, 30- and 31-weeks gestational age that did not have overt brain damage”
    “To determine whether COX2 was normally expressed in the developing human brain”

  • The paper relies on this without support.

    Nimesulide acts as a selective COX2 inhibitor.

    “Nimesulide (Sigma-Aldrich), a selective COX2 inhibitor”

  • The paper relies on this without support.

    The HIE cases with subcortical WMI represent human neonatal white matter injury.

    “term infant cases that suffered from hypoxic-ischemic encephalopathy (HIE) and matched controls”
    “all HIE cases in this study showed consistent evidence of diffuse white matter injury”

  • The paper relies on this without support.

    Nimesulide specifically inhibits COX2.

    “IL-1β-stimulated mixed glial cultures also produced PGE2 and this was inhibited by Nimesulide, which specifically targets COX2 (Supplementary Figure. 1 B).”

  • The paper relies on this without support.

    The human control cases with diaphragmatic hernia did not have gliosis or inflammatory infiltration despite possible milder hypoxia.

    “Our control cases included infants with diaphragmatic hernia, who may have been exposed to some milder degree of hypoxia that did not induce gliosis or inflammatory infiltration.”
5 of 5

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Inhibition of COX-2 has been confirmed to defend oligodendrocyte precursor cells under various damage conditions.

    “inhibition of this enzyme has been confirmed to defend oligodendrocyte precursor cells under various damage conditions [159,160].”

    From Beneficial Effects of Spirulina Consumption on Brain Health (2022) · cites this paper as [160]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Indomethacin course duration is impossible

    Minor

    The same courses are described as lasting both less than three days and greater than seven days.

1 of 1

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Authors
Shiow, L. R., Favrais, G., Schirmer, L., Schang, A., Cipriani, S., Andres, C., Wright, J. N., Nobuta, H., Fleiss, B., Gressens, P., & Rowitch, D. H.
Affiliations
  • University of California, San Francisco (US)
  • INSERM U930, Universite Francois Rabelais Tours France
  • Inserm (FR)
  • Université de Tours (FR)
  • Eli and Edythe Broad Center for Regeneration Medicine and Stem Cell Research, University of California San Francisco San Francisco California
  • St Thomas' Hospital (GB)
  • PROTECT, INSERM, Universite Paris Diderot, Sorbonne Paris Cite Paris France
Corresponding author
Rowitch, David H.
ORCID
Venue
Glia
Publisher
Wiley
Published
2017-08-30
Volume
65
Issue
12
Pages
2024-2037
ISSN
  • 0894-1491 (ISSN-L)
  • 1098-1136
DOI
10.1002/glia.23212
PMC
PMC5753598
OpenAlex
W2751534020
Semantic Scholar
403c16aa3ac2421a05c23d493a007bb94f35635b
Cited by
130
References
71
Citations by year
2026: 8 · 2025: 14 · 2024: 19 · 2023: 8 · 2022: 17 · 2021: 18 · 2020: 18 · 2019: 14 · 2018: 11 · 2017: 3
FWCI
13.74
Type
journal article
Language
en
Open access
Licence
onlinelibrary.wiley.com/termsAndConditions#vor (vor)
Locations
  • Glia (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
  • RMIT Research Repository (RMIT University Library) (submittedVersion)
  • Figshare (submittedVersion)
  • mediaTUM – the media and publications repository of the Technical University Munich (Technical University Munich) (submittedVersion)
  • Apollo (University of Cambridge) (submittedVersion)
  • Apollo
Funders
  • German Research Foundation (DFG, SCHI 1330/1-1)
  • Fondation Leducq
  • National Institute of Neurological Disorders and Stroke (P01NS083513)
  • Howard Hughes Medical Institute
Topics
  • Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Neonatal and fetal brain pathology
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Health Sciences › Medicine › Pharmacology › Inflammatory mediators and NSAID effects
Keywords
oligodendrocyte precursor cells, oligodendrocyte maturation, cyclooxygenase-2, prostaglandin E2, EP1 receptor, reactive astrocytes, IL-1β, hypoxic-ischemic encephalopathy, nimesulide, hypomyelination, cerebral palsy, neuroinflammation, neonatal neuroprotection
MeSH terms
Animals, Animals, Newborn, Astrocytes, Cells, Cultured, Female, Fetus, Glial Fibrillary Acidic Protein, Humans, L-Lactate Dehydrogenase, Male, Mice, Inbred C57BL, Mice, Transgenic, Oligodendroglia, Dinoprostone, Signal Transduction, Gene Expression Regulation, Developmental, Mice, Rats, Cyclooxygenase 2, Interleukin-1beta, Spatial Memory, White Matter

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-07.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-07.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

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