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Cited by 82Multiple Sclerosis Research StudiesNeurogenesis and neuroplasticity mechanismsMesenchymal stem cell research

Tamoxifen accelerates the repair of demyelinated lesions in the central nervous system

Open access
Gonzalez, Ginez A., Hofer, Matthias P., Syed, Yasir A., Amaral, Ana I., Rundle, Jon, Rahman, Saifur, Zhao, Chao, Kotter, Mark R. N.·2016·Scientific Reports
DOI 10.1038/srep31599PMC PMC4995517
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Abstract

Enhancing central nervous system (CNS) myelin regeneration is recognized as an important strategy to ameliorate the devastating consequences of demyelinating diseases such as multiple sclerosis. Previous findings have indicated that myelin proteins, which accumulate following demyelination, inhibit remyelination by blocking the differentiation of rat oligodendrocyte progenitor cells (OPCs) via modulation of PKCα. We therefore screened drugs for their potential to overcome this differentiation block. From our screening, tamoxifen emerges as a potent inducer of OPC differentiation in vitro. We show that the effects of tamoxifen rely on modulation of the estrogen receptors ERα, ERβ and GPR30. Furthermore, we demonstrate that administration of tamoxifen to demyelinated rats in vivo accelerates remyelination. Tamoxifen is a well-established drug and is thus a promising candidate for a drug to regenerate myelin, as it will not require extensive safety testing. In addition, Tamoxifen plays an important role in biomedical research as an activator of inducible genetic models. Our results highlight the importance of appropriate controls when using such models.

AI snapshot

Written from the paper’s full text.

TL;DR

Tamoxifen promotes oligodendrocyte progenitor cell (OPC) differentiation and accelerates remyelination in vitro and in a rat demyelination model, acting via estrogen receptors ERα, ERβ, and GPR30 rather than PKCα. Because tamoxifen is already clinically used, the authors propose it as a candidate remyelination therapy and caution that it may confound inducible CreERT2 models.

Key findings

  • In a screen of PKCα inhibitors, tamoxifen (50 nM) increased MBP+ and CNP+ cells and induced Mbp mRNA expression; the increase in MBP+ cells was concentration dependent.
  • siRNA silencing of Er-α, Er-β, or Gpr30 reduced OPC differentiation and reduced tamoxifen-induced differentiation, whereas PKCα silencing did not reduce tamoxifen-induced differentiation and transiently increased Mbp expression at day 4.
  • In vivo, the higher tamoxifen dose (2 mg/kg/day) significantly increased cells expressing mature oligodendrocyte markers APC(CC1) and Plp at 14 days post lesion induction (pli); blinded rank analysis and axon counts showed significantly more remyelinated axons at 14 days pli, with no difference in relative myelin thickness.
  • Tamoxifen did not alter osteopontin-positive macrophage presence, CCR7+ M1 or Arginase1+ M2 macrophage numbers, or Oil Red-O-labeled myelin-derived neutral lipid phagocytosis at 7 days pli.

Methods

  • Primary OPC cultures were isolated from neonatal Sprague Dawley rat forebrains (postnatal day 0–3), with sex-segregated cultures used to compare ER expression; only cultures with ≥94% purity were used, and differentiation was induced in Sato’s medium with 0.5% fetal calf serum.
  • In vitro experiments used PKC inhibitors including tamoxifen at 50 nM, siRNA against ERα, ERβ, GPR30, and PKCα, plus immunocytochemistry and qRT-PCR for differentiation markers.
  • In vivo, female Sprague Dawley rats in estrum (200–220 g) received bilateral stereotactic ethidium bromide lesions in the caudal cerebellar peduncle; tamoxifen was injected intraperitoneally at 0.5 mg/kg/day or 2 mg/kg/day from 3 days pli for 11 days, with analysis at 7 and 14 days pli using in situ hybridization, immunohistochemistry, resin histology, electron microscopy, and blinded quantification; only lesions larger than 0.2 mm² were included.

Limitations

  • Stated in the paper: only young adult female rats were used in vivo, so indirect systemic effects and possible different responses in male rats cannot be ruled out; astrocytes were not evaluated; and further indirect effects of tamoxifen, such as altered cytokine or chemokine release, cannot be entirely excluded.
  • Stated in the paper: fetal calf serum components or testosterone conversion could activate estrogen receptors in a ligand-independent manner in vitro, complicating interpretation of ER silencing; the transient increase in MBP with PKCα silencing plus tamoxifen was observed at only a single time point.
  • Evident from the text: the in vivo model uses ethidium bromide-induced focal demyelination rather than an autoimmune multiple sclerosis model, and the study reports histological/ultrastructural remyelination outcomes rather than clinical or functional outcomes.

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

Integrity signals

Registry

Crossref · 10.1038/srep31599

Cites

54 of 54 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

9 of 25 cited sources checked · 5 supported · 0 flagged · accuracy not yet measured

  • Premisecitation

    Administration of progesterone to cerebellar slices after lysolecithin-induced demyelination showed an increase in remyelination.

    “Furthermore, there is evidence that steroid hormones promote myelin repair: administration of progesterone to cerebellar slices after lysolecithin-induced demyelination showed an increase in remyelination50”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [50] Hussain, R. et al. Progesterone and Nestorone facilitate axon remyelination: a role for progesterone receptors. Endocrinology. 152, 3820–3831 (2011). source
  • Premisecitation

    Fetal calf serum used in OPC media contains several components that could activate estrogen receptors in a ligand-independent manner.

    “However, fetal calf serum (FCS) used in the OPC media does contain several components, which could activate estrogen receptors in a ligand-independent manner. Picard 2003, describes a list of molecules which could cross-talk with the estrogen receptors without physically interacting with them, for example, insulin (which forms an important component of the differentiation medium), IGF and FGF42.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [42] Picard, D. SCOPE/IUPAC project on environmental implications of endocrine active substances: Molecular mechanisms of cross-talk between growth factors and nuclear receptor signaling. Pure Appl Chem 75, 1743–1756 (2003). source
  • Premisecitation

    Inhibition of PKCs does not promote differentiation by itself when cells are cultured in serum-containing media.

    “Our results also confirm previous reports22 that the inhibition of PKCs does not promote differentiation by itself when cells are cultured in serum containing media.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [22] Baer, A. S. et al. Myelin-mediated inhibition of oligodendrocyte precursor differentiation can be overcome by pharmacological modulation of Fyn- RhoA and protein kinase C signalling. Brain. 132, 465–481 (2009). source

      The Results section reports that PKC inhibitors promoted oligodendrocyte precursor differentiation in the presence of myelin inhibitors. It does not report whether PKC inhibition alone promotes differentiation in serum-containing medium; searches for serum and for treatment on a control substrate did not establish that comparison. Page numbers were not available in our copy. (LLM, conf=0.76)

      Experimental — accuracy not yet measured
  • Findingcitation

    In PBS-treated animals, inclusion of lesions smaller than 0.2 mm2, which were strongly populated with Plp-positive cells, resulted in a significant non-zero slope indicating an effect of lesion size on Plp-positive cell density.

    “The inclusion of lesions smaller than 0.2 mm2, which were strongly populated with Plp-positive cells, resulted in a significant non-zero slope indicating an effect of the lesion size on the cell density, as shown in previous studies14.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [14] Syed, Y. A. et al. Inhibition of phosphodiesterase-4 promotes oligodendrocyte precursor cell differentiation and enhances CNS remyelination. EMBO Mol Med. 5, 1918–1934 (2013). source

      The Methods section (Induction of focal demyelination; page not provided) reports the analysis in PBS-treated animals and a significant non-zero slope for Plp-positive cell density. It gives the lesion-size cutoff as <0.4 mm², however, not <0.2 mm². (LLM, conf=0.90)

      Experimental — accuracy not yet measured
  • Premisecitation

    The efficiency of remyelination is inversely correlated with lesion size.

    “Since the efficiency of remyelination is inversely correlated with lesion size, this model is advantageous for studying the kinetics of CNS remyelination36.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [36] Syed, Y. A. et al. Inhibition of CNS remyelination by the presence of semaphorin 3A. J Neurosci. 31, 3719–3728 (2011). source

      In “Infusion of Sema3A into demyelinated lesions” (page unavailable), the authors suggest that remyelination may be more efficient in small lesions than in larger ones. But their measured correlation was between lesion size and PLP-positive cell density, and they found no significant correlation for lesions larger than 0.4 mm². The claim overstates this as a general inverse correlation between lesion size and remyelination efficiency. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
  • Classified as probably not a substantial claim. 18
  • May combine two claims. 16

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

    Premisecitation

    Inhibition of PKCα only shows effects in the presence of inhibitory myelin substrates.

    “This was expected as with the culture conditions applied, inhibition of PKCα only shows effects in the presence of inhibitory myelin substrates22.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [22] Baer, A. S. et al. Myelin-mediated inhibition of oligodendrocyte precursor differentiation can be overcome by pharmacological modulation of Fyn- RhoA and protein kinase C signalling. Brain. 132, 465–481 (2009). source

      The Results section, “PKC inhibitors promote OPC differentiation in the presence of myelin inhibitors” (page unavailable), reports that PKC inhibitors and PKC-α silencing increased OPC differentiation on myelin substrates. It does not establish the claim’s “only” qualifier: that PKC-α inhibition has no effect without an inhibitory myelin substrate. (LLM, conf=0.85)

      Experimental — accuracy not yet measured

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

    Premisecitation

    GPR30 modulates several signaling pathways such as the phosphatidylinositol-3 kinase and mitogen-activated protein kinase pathways.

    “GPR30 is known to modulate several signaling pathways such as the phosphatidylinositol-3 kinase and mitogen-activated protein kinase pathways25.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [25] Prossnitz, E. R. & Barton, M. The G-protein-coupled estrogen receptor GPER in health and disease. Nat Rev Endocrinol. 7, 715–726 (2011). source

  • May combine two claims.

    Premisecitation

    In the presence of myelin debris, inhibition of PKCα neutralizes myelin-associated inhibitors and promotes differentiation.

    “Conversely, in the presence of myelin debris, the inhibition of PKCα neutralizes myelin-associated inhibitors and promotes differentiation22.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [22] Baer, A. S. et al. Myelin-mediated inhibition of oligodendrocyte precursor differentiation can be overcome by pharmacological modulation of Fyn- RhoA and protein kinase C signalling. Brain. 132, 465–481 (2009). source

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

    Premisecitation

    Administration of progesterone promotes myelin regeneration in chronic demyelinated lesions in the corpus callosum of mice after cuprizone feeding.

    “and recently, the same group has shown that administration of progesterone promotes myelin regeneration in chronic demyelinated lesions in the corpus callosum of mice after being fed with cuprizone51.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [51] El-Etr, M. et al. Progesterone and nestorone promote myelin regeneration in chronic demyelinating lesions of corpus callosum and cerebral cortex. Glia. 63, 104–117 (2015). source

  • May combine two claims.

    Findingown data

    Tamoxifen increased the number of MBP+ and CNP+ cells on control and myelin substrates respectively.

    “Addition of tamoxifen to OPCs plated on control substrates or to cells on myelin substrates increased the number of MBP+ and CNP+ cells respectively (Fig. 1c, e–i).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    ERα, ERβ, GPR30, and active PKCα are present in oligodendrocyte lineage cells within remyelinating lesions.

    “This confirmed the presence of all three ERs and active PKCα in oligodendrocyte lineage cells within remyelinating lesions (Fig. 4).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    We did not observe changes in the number of recruited cells or the myelin debris removal at 7 and 14 pli.

    “We did not observe changes in the number of recruited cells or the myelin debris removal at 7 and 14 pli.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Among the PKCα inhibitors tested, tamoxifen most effectively promoted OPC differentiation, albeit via an alternative mechanism.

    “We found that tamoxifen promoted this most effectively, albeit via an alternative mechanism.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    Tamoxifen has been used for the treatment of breast cancer since the early 1970s.

    “Tamoxifen has been used for the treatment of breast cancer since the early 1970s23.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [23] Clemons, M., Danson, S. & Howell, A. Tamoxifen (“Nolvadex”): a review. Cancer Treat Rev. 28, 165–180 (2002). source

  • May combine two claims.

    Premisecitation

    Barrat et al. found that all metabolites of tamoxifen (4-hydroxytamoxifen and endoxifen) as well as tamoxifen citrate promoted expression of late stage markers of OPC differentiation such as Cnp and Mbp.

    “They found that all metabolites promoted the expression of late stage markers of OPC differentiation, such as Cnp and Mbp, which is consistent with our findings using primary rat OPC cultures.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [43] Barratt, H. E. et al. Tamoxifen promotes differentiation of oligodendrocyte progenitors in vitro. Neuroscience, 319, 146–154 (2016). source

  • May combine two claims.

    Interpretationcitation

    These data support the positive effects of steroid hormones and their potential for the treatment of demyelinating diseases.

    “These data support the positive effects of steroid hormones and their potential for the treatment of demyelinating diseases.”
    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

    Sex-segregated cultures were prepared from female and male only pups, and male-derived OPCs were confirmed by SRY genotyping.

    “Sex-segregated cultures were prepared from female and male only pups. The male-derived OPCs was confirmed by genotyping for the presence of the SRY gene, present only in the Y chromosome (data not shown).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    The literature indicates that sex-related differences exist with respect to the efficiency of remyelination: in young rats the rate of remyelination is comparable between the sexes, but it is more efficient in aged female rats as compared to male rats.

    “The literature indicates that sex-related differences exist with respect to the efficiency of remyelination: whilst in young rats the rate of remyelination is comparable between the sexes, it is more efficient in aged female rats as compared to male rats44.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [44] Li, W. W., Penderis, J., Zhao, C., Schumacher, M. & Franklin, R. J. Females remyelinate more efficiently than males following demyelination in the aged but not young adult CNS. Exp Neurol. 202, 250–254 (2006). source

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

    Study design and conductown data

    The analysis of remyelinated axons was performed with investigator blinding.

    “Investigator-blinded rank analysis demonstrated that tamoxifen significantly increased the number of remyelinated axons (Fig. 6a).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Testosterone present in fetal calf serum could be converted by aromatase, expressed in low levels in glial cells, into estrogen and therefore activate all estrogen receptors.

    “Moreover, testosterone (present in FCS) could be converted by aromatase, which is expressed in low levels in glial cells (http://web.stanford.edu/group/barres_lab/brain_rnaseq.html), into estrogen and therefore, activate all estrogen receptors.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites http://web.stanford.edu/group/barres_lab/brain_rnaseq.html

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

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

    Premisecitation

    Tamoxifen can act as an agonist or antagonist on estrogen receptors depending on the cell type.

    “An interesting property of tamoxifen is that, depending on the cell type, it can act as agonist or antagonist on estrogen receptors35.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [35] Smith, C. L. & O’Malley, B. W. Coregulator function: a key to understanding tissue specificity of selective receptor modulators. Endocr Rev. 25, 45–71 (2004). source

  • May combine two claims.

    Interpretationown data

    Tamoxifen exerts OPC-differentiation-inducing effects via estrogen receptors but not via PKCα.

    “Tamoxifen therefore seems to exert OPC-differentiation-inducing effects via ERs but not via PKCα.”
    • Also stated in: § Discussion · plain
      “The effects of tamoxifen do not involve the PKCα pathway.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    In small lesions, recruitment of OPCs and clearance of myelin debris are more efficient, and thus remyelination becomes more efficient than with larger lesions.

    “This may be explained by the fact that in small lesions, recruitment of OPCs and the clearance of myelin debris are more efficient, and thus remyelination becomes more efficient than with larger lesions.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    All quantifications in immunohistochemical analysis in vivo were conducted with the investigators blind to treatment group.

    “All quantifications were conducted with the investigators blind to the treatment group.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

    Study design and conductnone given

    Dissolved small molecule stock solutions were diluted at least 1:10000 when added to cells, eliminating side effects of the dissolving agent.

    “Dissolved small molecule stock solutions were diluted at least by 1:10000 when added to the cells eliminating eventual side effect of the dissolving agent.”
    Quote in the paperNot a substantial claim

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

    Study design and conductnone given

    For all in vitro experiments, only cultures with at least 94% purity were used.

    “For all in vitro experiments, only cultures with ≥94% purity were used.”
    Quote in the paperNot a substantial claim

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

    Study design and conductnone given

    Concentrations of PKC inhibitors were determined in independent dose-finding experiments.

    “Concentrations of the PKC inhibitors were determined in independent dose-finding experiments.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    The effect of tamoxifen was blocked when a pan-antagonist was added to the media, supporting that tamoxifen acts as an estrogen receptor agonist in OPC differentiation.

    “In addition, the effect of tamoxifen was blocked when a pan-antagonist was added to the media, supporting our finding that tamoxifen acts as an estrogen receptor agonist in OPC differentiation.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [43] Barratt, H. E. et al. Tamoxifen promotes differentiation of oligodendrocyte progenitors in vitro. Neuroscience, 319, 146–154 (2016). source

  • Classified as probably not a substantial claim.

    Study design and conductown data

    Lesions were ranked according to extent of remyelination by two blinded investigators.

    “Lesions were ranked according to the extent of remyelination by two blinded investigators and statistically analyzed using a two-tailed Mann–Whitney test.”
    Quote in the paperSubstantial claim

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

    Study design and conductnone given

    qRT-PCR measurements were made in triplicate on three biological replicates.

    “Triplicate measurements were made on three biological replicates.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Administration of estriol to nonpregnant women with RRMS showed a reduction in the number of Th1 cells and in the clinical score of the disease.

    “Interestingly, the administration of estriol to nonpregnant women with RRMS showed a reduction in the number of Th1 cells, which are involved in the autoimmune response, and also in the clinical score of the disease49.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [49] Sicotte, N. L. et al. Treatment of multiple sclerosis with the pregnancy hormone estriol. Ann Neurol. 52, 421–428 (2002). source

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

    Premisecitation

    During pregnancy, a reduction in the frequency of relapse rate in patients with relapsing-remitting MS (RRMS) has been reported.

    “During pregnancy, a reduction in the frequency of relapse rate in patients with relapsing–remitting MS (RRMS) has been reported454647.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites 454647

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

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

    Study design and conductown data

    The investigator assessing OPC differentiation was blind to treatment group.

    “with the investigator being blind to treatment group”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    A decrease in the severity of symptoms in comparison with a nonpregnant control group was detected in pregnant mice affected by experimental autoimmune encephalomyelitis.

    “Similarly, a decrease in the severity of the symptoms in comparison with a nonpregnant control group was detected in pregnant mice affected by experimental autoimmune encephalomyelitis, a model of the autoimmune destruction of myelin sheaths occurring in MS48.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [48] Voskuhl, R. R. & Palaszynski, K. Sex hormones in experimental autoimmune encephalomyelitis: implications for multiple sclerosis. Neuroscientist. 7, 258–270 (2001). source

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

    Study design and conductnone given

    All analyses in in situ hybridization were conducted with the investigator blind to treatment group.

    “All analyses were conducted with the investigator blind to the treatment group.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    ERα and ERβ are estrogen-responsive nuclear receptors that act as transcriptional regulators.

    “Whereas ERα and ERβ are estrogen-responsive nuclear receptors that act as transcriptional regulators24,”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [24] Heldring, N., Pike, A., Andersson, S. et al. Estrogen receptors: how do they signal and what are their targets. Physiol Rev. 87, 905–931 (2007). source
31 of 31

  • The paper relies on this without support.

    Tamoxifen modulates estrogen signaling.

    “In addition to inhibiting PKCα activity, tamoxifen is known to modulate estrogen signaling (Fig. 2a).”

  • The paper relies on this without support.

    Tamoxifen inhibits PKCα activity.

    “In addition to inhibiting PKCα activity, tamoxifen is known to modulate estrogen signaling (Fig. 2a).”

  • The paper relies on this without support.

    Tamoxifen has an excellent safety profile.

    “For example, it has an excellent safety profile that has undergone the test of time by exhaustive application in the clinic.”

  • The paper relies on this without support.

    Tamoxifen plays an important role in biomedical research as an activator of inducible genetic models.

    “In addition, Tamoxifen plays an important role in biomedical research as an activator of inducible genetic models.”

  • The paper relies on this without support.

    Multiple sclerosis often affects female patients.

    “The main reasons why we decided to use female rats in our study were comparability to previous studies and the fact that MS often affects female patients.”

  • The paper relies on this without support.

    Estrogen signalling plays a distinctive role in females.

    “Estrogen signalling plays a distinctive role in females.”

  • The paper relies on this without support.

    The majority of reported pharmacological studies of tamoxifen use the free base form and not soluble forms.

    “The majority of the reported pharmacological (metabolism and toxicology) studies of tamoxifen use the free base form of tamoxifen and not the soluble forms (citrate tamoxifen and/or 4-OH tamoxifen).”
7 of 7

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?

  • Tamoxifen has shown neuroprotective effects in models of stroke, dementia, multiple sclerosis, Parkinson's disease, traumatic brain injury, and spinal cord injury.

    “tamoxifen crosses the blood-brain barrier [32] and has shown neuroprotective effects in models of stroke [33], dementia [34], multiple sclerosis [35], Parkinson’s disease [36], traumatic brain injury [37], and SCI [38].”

    From Delayed short-term tamoxifen treatment does not promote remyelination or neuron sparing after spinal cord injury (2020) · cites this paper as [35]

    The Results section reports that tamoxifen accelerated remyelination in rats with experimentally induced CNS lesions, a finding relevant to multiple sclerosis. But the study used an ethidium-bromide demyelination model, not a model of multiple sclerosis itself, and measured myelin repair rather than a direct neuroprotective effect. Citation [35] is attached only to the multiple-sclerosis part of the citing sentence; the other conditions are outside this verdict. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • Following 8 days of treatment with ifenprodil or tamoxifen, remyelination was widespread throughout the lesion.

    “By contrast, following 8 days of treatment with ifenprodil or tamoxifen, remyelination was widespread throughout the lesion”

    From Accumulation of 8,9-unsaturated sterols drives oligodendrocyte formation and remyelination (2018) · cites this paper as [9]

    The Results (‘Tamoxifen promotes CNS remyelination’; page unavailable) report increased remyelinated axons at 14 days post-lesion with tamoxifen. The Methods (‘Induction of focal demyelination’; page unavailable) specify treatment from day 3 through day 14, not 8 days. Our copy does not establish widespread remyelination throughout the lesion or an effect of ifenprodil. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • Tamoxifen injected intraperitoneally in adult female rats acutely after toxin-induced demyelination in the brain stimulated NG2+ oligodendrocyte progenitor cell differentiation into oligodendrocytes and accelerated the rate of remyelination.

    “tamoxifen injected intraperitoneally in adult female rats acutely after toxin-induced demyelination in the brain stimulated NG2+ oligodendrocyte progenitor cell differentiation into oligodendrocytes [OLs] and accelerated the rate of remyelination [35].”

    From Delayed short-term tamoxifen treatment does not promote remyelination or neuron sparing after spinal cord injury (2020) · cites this paper as [35]

  • In the ethidium bromide model of demyelination, tamoxifen stimulates OL differentiation and increases the number of remyelinated axons in rats.

    “In the ethidium bromide model of demyelination, tamoxifen stimulates OL differentiation and increases the number of remyelinated axons in rats [35].”

    From Delayed short-term tamoxifen treatment does not promote remyelination or neuron sparing after spinal cord injury (2020) · cites this paper as [35]

  • Since tamoxifen promotes OL differentiation and remyelination, it is possible that inducing Cre-recombination with tamoxifen artificially inflates the extent of remyelination.

    “Since tamoxifen promotes OL differentiation and remyelination [35], it is possible that inducing Cre-recombination with tamoxifen artificially inflates the extent of remyelination.”

    From Delayed short-term tamoxifen treatment does not promote remyelination or neuron sparing after spinal cord injury (2020) · cites this paper as [35]

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.

  • In vivo tamoxifen doses are reported in conflicting units

    Major

    The Results report doses of 0.5 and 2 mg per day, while the Methods report the same numerical doses per kilogram per day. For the stated 200-220 g rats, these are substantially different administered amounts.

1 of 1

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Authors
Gonzalez, G. A., Hofer, M. P., Syed, Y. A., Amaral, A. I., Rundle, J., Rahman, S., Zhao, C., & Kotter, M. R. N.
Affiliations
Wellcome/MRC Cambridge Stem Cell Institute (GB)
ORCID
Venue
Scientific Reports
Publisher
Springer Science and Business Media LLC
Published
2016-08-24
Volume
6
Issue
1
Pages
31599-31599
ISSN
2045-2322 (ISSN-L)
DOI
10.1038/srep31599
PMC
PMC4995517
OpenAlex
W2513554498
Semantic Scholar
5e247a6ee6ebe990a6bb706ec82aa5a85fab5da1
Cited by
82
References
54
Citations by year
2025: 7 · 2024: 6 · 2023: 7 · 2022: 7 · 2021: 10 · 2020: 14 · 2019: 13 · 2018: 8 · 2017: 9 · 2016: 1
FWCI
8.10
Type
journal article
Language
en
Open access
Licence
Locations
  • Scientific Reports (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • ORCA Online Research @Cardiff (Cardiff University) (acceptedVersion)
  • PubMed Central (submittedVersion, cc-by)
  • Apollo (University of Cambridge) (submittedVersion, cc-by)
  • Apollo (cc-by)
Funders
  • Wellcome Trust
  • National Institute for Health and Care Research (CS-2015-15-023)
  • Multiple Sclerosis Society
  • University of Cambridge
  • Medical Research Council (MC_PC_12009)
  • Comisión Nacional de Investigación Científica y Tecnológica
Topics
  • Health Sciences › Medicine › Pathology and Forensic Medicine › Multiple Sclerosis Research Studies
  • Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
  • Health Sciences › Medicine › Genetics › Mesenchymal stem cell research
Keywords
tamoxifen, remyelination, demyelination, oligodendrocyte precursor cells, OPC differentiation, protein kinase C alpha, estrogen receptor alpha, estrogen receptor beta, GPR30, multiple sclerosis, central nervous system demyelinating diseases, drug screening
MeSH terms
Animals, Cell Differentiation, Demyelinating Diseases, Oligodendroglia, Tamoxifen, Rats, Sprague-Dawley, Rats, Neural Stem Cells

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 2026-10-11.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-11.

Cited sources are checked by gpt-6-sol.

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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