Glial response during cuprizone-induced de- and remyelination in the CNS: lessons learned

FAS is not essential for the induction of apoptosis in the cuprizone model.

“However, oligodendrocyte death was not prevented in mice lacking FAS in oligodendrocytes revealing that FAS is also not essential for the induction of apoptosis in the cuprizone model (Hesse et al., 2010).”

• cites Hesse et al., 2010 sourceSupported

Female SJL mice are partially resistant to demyelination in the corpus callosum despite similar extent of astro- and microgliosis and OPC response in both genders.

“Additionally, despite of a similar extent of astro- and microgliosis as well as OPC response in both genders, female SJL mice were partially resistant to the demyelination in the CC.”

• cites Taylor et al., 2010 sourcePartly supported

  The Discussion (page unavailable) reports that female SJL mice had less severe demyelination than males, citing an earlier study. The passages on astrocytes and microglia (pages unavailable) find similar responses between sexes in C57BL/6 mice, not SJL mice; our copy does not establish a similar OPC response in SJL mice. (LLM, conf=0.87)

  Experimental — accuracy not yet measured

During cuprizone-induced demyelination, oligodendrocytes start to undergo apoptosis after 3-7 days of cuprizone exposure.

“During cuprizone-induced demyelination, oligodendrocytes start to undergo apoptosis after 3–7 days of cuprizone exposure (Mason et al., 2000a; Komoly, 2005; Hesse et al., 2010).”

• cites Mason et al., 2000a sourceNot checked — no full text of the source
• cites Komoly, 2005Not checked — no full text of the source
• cites Hesse et al., 2010 sourcePartly supported

  The Results section reports apoptotic oligodendrocytes on day 6, within the claimed 3–7-day window. But it also reports apoptotic oligodendrocytes 2 days after the diet began, so the paper does not support 3–7 days as the time apoptosis starts. (LLM, conf=0.87)

  Experimental — accuracy not yet measured

Once demyelination is complete, the amount of activated RCA-1/Mac-3-positive microglia starts to decrease.

“Once demyelination is complete the amount of activated RCA-1 (RCA, Ricinus communis agglutinin-1)/Mac-3-positive microglia starts to decrease (Mason et al., 2004; Skripuletz et al., 2011b).”

• cites Mason et al., 2004 sourcePartly supported

  In “The Presence of Microglia/Macrophages Coincides with Demyelination and Oligodendrocyte Death” (page not available), RCA-1-positive microglia/macrophages decline after mice return to a normal diet. But their numbers remain elevated in chronically demyelinated mice kept on cuprizone, so completion of demyelination alone does not establish the claimed decline. The paper identifies these cells with RCA-1, not Mac-3. (LLM, conf=0.87)

  Experimental — accuracy not yet measured
• cites Skripuletz et al., 2011b sourceNot checked — no full text of the source

Up-regulation of MHC-II at the peak of demyelination may be relevant for the induction of remyelination.

“The up-regulation of MHC-II at the peak of demyelination may be of relevance for the induction of remyelination since MHC-II −/− mice showed delayed remyelination and regeneration of oligodendrocytes after cuprizone-induced demyelination (Arnett et al., 2003).”

• cites Arnett et al., 2003 sourceSupported

MHC-II −/− mice showed delayed remyelination and regeneration of oligodendrocytes after cuprizone-induced demyelination.

“MHC-II −/− mice showed delayed remyelination and regeneration of oligodendrocytes after cuprizone-induced demyelination (Arnett et al., 2003).”

• cites Arnett et al., 2003 sourceSupported

Upon chronic cuprizone administration (12-16 weeks), newly generated oligodendrocytes progressively undergo apoptosis.

“Upon chronic cuprizone administration (12–16 weeks) newly generated oligodendrocytes progressively undergo apoptosis.”

• cites Mason et al., 2004 sourcePartly supported

  The section “The Mature Oligodendrocyte Population Is Inadequately Regenerated within Chronically Demyelinated Lesion” reports apoptotic oligodendrocytes during prolonged cuprizone feeding, and Figure 2 quantifies them through 12 weeks. Although “Induction of Acute and Chronic Demyelination” says mice were fed cuprizone for up to 16 weeks, the cited passages do not establish that newly generated oligodendrocytes progressively underwent apoptosis throughout the stated 12–16-week period. Page numbers are unavailable in our copy. (LLM, conf=0.84)

  Experimental — accuracy not yet measured

After 3 weeks of cuprizone treatment, mature oligodendrocytes are almost completely depleted.

“After 3 weeks of cuprizone treatment mature oligodendrocytes are almost completely depleted (Hesse et al., 2010; Skripuletz et al., 2011b).”

• cites Hesse et al., 2010 sourceSupported
• cites Skripuletz et al., 2011b sourceNot checked — no full text of the source

Upon chronic cuprizone administration, the pool of OPC becomes diminished.

“Furthermore, also the pool of OPC becomes diminished (Mason et al., 2004).”

• cites Mason et al., 2004 sourceSupported

Similar associations between microglial activation and OPC accumulation are observed in post-mortem tissue from MS patients and in EAE challenged animals.

“Similar associations are also observed in post-mortem tissue from MS patients and in EAE challenged animals (Prineas and Connell, 1979; Nishiyama et al., 1997; Wolswijk, 2002; Patani et al., 2007).”

• cites Prineas and Connell, 1979 sourceNot checked — no full text of the source
• cites Nishiyama et al., 1997 sourceNot checked — no full text of the source
• cites Wolswijk, 2002 sourcePartly supported

  In the section on factors influencing OPC density (page not available), Wolswijk reports a positive correlation between OPC and macrophage densities in lesions from people with chronic MS. The tissue-characteristics section also identifies activated microglia/macrophages in the samples. The paper does not report the claimed association in EAE-challenged animals, so it supports only the post-mortem MS-tissue portion of the sentence. (LLM, conf=0.85)

  Experimental — accuracy not yet measured

Demyelinated axons retain the ability to be remyelinated.

“Nevertheless, demyelinated axons retain the ability to be remyelinated as shown by transplantation of OPC into the lesions (Mason et al., 2004).”

• cites Mason et al., 2004 sourceSupported

Activated microglia persist at a low level in chronically demyelinated lesions in mice treated with cuprizone up to 12 weeks.

“In contrast, activated microglia persist at a low level in chronically demyelinated lesions in mice treated with cuprizone up to 12 weeks (Mason et al., 2004; Lindner et al., 2009).”

• cites Mason et al., 2004 sourcePartly supported

  The Figure 4 caption reports a few RCA-1-positive microglia/macrophages in the chronically demyelinated corpus callosum after 12 weeks of cuprizone feeding. The section on microglia/macrophages says their numbers remained elevated relative to controls. The paper supports persistence at a low level, but these passages do not establish that the cells were specifically activated microglia rather than microglia/macrophages. (LLM, conf=0.84)

  Experimental — accuracy not yet measured
• cites Lindner et al., 2009 sourceNot checked — no full text of the source

In response to cuprizone, a very small number of T cells was recruited to the demyelinated corpus callosum.

“Indeed, in response to cuprizone a very small number of T cells was recruited to the demyelinated CC and these T cells did not display an activated phenotype (Remington et al., 2007).”

• cites Remington et al., 2007 sourceSupported

Cuprizone-induced de- and remyelination are not mediated by B or T cells.

“Overall, cuprizone-induced de- and remyelination are not mediated by B or T cells, as shown by the use of RAG −/− mice that lack lymphocytes (Arnett et al., 2001; Hiremath et al., 2008).”

• cites Arnett et al., 2001 sourceNot checked — no full text of the source
• cites Hiremath et al., 2008 sourcePartly supported

  The Results section (‘T cells are not required for activating MHC II’; page unavailable) reports that cuprizone-treated RAG-1−/− mice, which lack B and T cells, had demyelination similar to wild-type mice. The Discussion says T cells do not play a role in remyelination, citing Arnett et al. (2001), but this paper does not report a RAG-1−/− remyelination comparison or establish the same conclusion for B cells during remyelination. (LLM, conf=0.85)

  Experimental — accuracy not yet measured

Strong astrogliosis comprising hypertrophy and hyperplasia of astrocytes occurs as a response to cuprizone treatment in different white and gray matter structures including the corpus callosum, hippocampus, cerebellum, cortex, and basal ganglia.

“Strong astrogliosis comprising hypertrophy and hyperplasia of astrocytes occurs as a response to cuprizone treatment in different white and gray matter structures for instance the CC (Matsushima and Morell, 2001; Gudi et al., 2009), hippocampus, (Koutsoudaki et al., 2009; Norkute et al., 2009), cerebellum, cortex (Skripuletz et al., 2008), and basal ganglia (Pott et al., 2009).”

• cites Matsushima and Morell, 2001 sourceCould not verify

  The available summary describes cuprizone-induced demyelination, microglial recruitment, and remyelination, but does not describe astrogliosis in the corpus callosum. Searches for astrocyte hypertrophy, hyperplasia, astrogliosis, and corpus callosum found no passage establishing the response attributed to Matsushima and Morell; the other named regions have separate citations in the citing sentence. (LLM, conf=0.70)

  Experimental — accuracy not yet measured
• cites Gudi et al., 2009 sourceNot checked — no full text of the source
• cites Skripuletz et al., 2008 sourcePartly supported

  Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

  Experimental — accuracy not yet measured

A subset of peripheral macrophages (CD11b+/CD45high) infiltrated into the demyelinated corpus callosum of cuprizone-treated mice.

“In contrast, a subset of peripheral macrophages (CD11b+/CD45high) infiltrated into the demyelinated CC of cuprizone-treated mice (McMahon et al., 2002; Remington et al., 2007).”

• cites McMahon et al., 2002 sourceNot checked — no full text of the source
• cites Remington et al., 2007 sourceSupported

T cells recruited to the demyelinated corpus callosum did not display an activated phenotype.

“these T cells did not display an activated phenotype (Remington et al., 2007)”

• cites Remington et al., 2007 sourceSupported

Only 0.5% of the CD11b+ population is CD45high and thus represents infiltrating macrophages.

“Remington and co-workers reported that only 0.5% of the CD11b+ population is CD45high and thus represents infiltrating macrophages.”

• cites Remington et al., 2007 sourcePartly supported

  The Macrophage/Microglial Response section reports that, at 4.5 weeks of cuprizone treatment, CD45-dim microglia comprised 99.5% of CD11b-positive cells in the corpus callosum; it identifies CD45-high cells as blood-derived macrophages. The remaining approximately 0.5% supports the figure, but the citing sentence omits the treatment and time point that bound it. (LLM, conf=0.85)

  Experimental — accuracy not yet measured

In the cuprizone model, microglia seem not to be assigned to a certain phenotype characteristic either for de- or remyelination, since most regulated genes showed unidirectional up-regulation or down-regulation throughout de- and remyelination.

“In addition, in this model microglia seem not to be assigned to a certain phenotype characteristic either for de- or remyelination since most of the genes that were regulated showed an unidirectional up-regulation or down-regulation throughout the de- and remyelination processes (Olah et al., 2012)”

• cites Olah et al., 2012 sourceSupported

In chronic cuprizone lesions there are no signs of astroglial scar properties.

“however, in chronic cuprizone lesions there are no signs of astroglial scar properties (Hibbits et al., 2012).”

• cites Hibbits et al., 2012 sourcePartly supported

  The Discussion says cuprizone lesions lacked an astroglial scar interface with fibrillar collagen, and the Results report no collagen fibrils in chronic lesions. But the Results also report increased scar-associated extracellular matrix molecules, while the Discussion describes a dense network of GFAP- and Vim-expressing astrocyte processes in chronic lesions. Thus, the paper supports the absence of a fibrotic scar, not the absence of all astroglial scar properties. (LLM, conf=0.88)

  Experimental — accuracy not yet measured

CD247 (B7-H1) was up-regulated on microglia throughout de- and remyelination.

“Olah and colleges have shown that CD247 (B7-H1), a known immune inhibitory molecule (Magnus et al., 2005; Ortler et al., 2008) was up-regulated on microglia throughout de- and remyelination (Olah et al., 2012).”

• cites Olah et al., 2012 sourceSupported

Axl and Mer were found on activated microglia.

“while Axl and Mer were found on activated microglia (Binder et al., 2008)”

• cites Binder et al., 2008 sourceSupported

In untreated mice, Tyro3 co-localizes with CNPase.

“In untreated mice Tyro3 co-localizes with CNPase.”

• cites Binder et al., 2008 sourceSupported

IL-1β did not display any impact on depletion of oligodendrocytes following cuprizone treatment.

“Additionally, IL-1β did not display any impact on depletion of oligodendrocytes following cuprizone treatment (Mason et al., 2001).”

• cites Mason et al., 2001 sourceSupported

Remyelination was enhanced when LtβR-signaling was inhibited by an LtβR-Ig fusion decoy protein.

“Surprisingly, remyelination was enhanced when LtβR-signaling was inhibited by an LtβR-Ig fusion decoy protein.”

• cites Plant et al., 2007 sourceSupported

In the cuprizone model, IL-1β was gradually up-regulated from the first week of cuprizone intoxication, then strongly increased at week 3 and sustained on this level until week 6.

“In the cuprizone model IL-1β was gradually up-regulated from the first week of cuprizone intoxication, then strongly increased at week 3 and sustained on this level until week 6 (Mason et al., 2001).”

• cites Mason et al., 2001 sourcePartly supported

  The section “Expression of IL-1β precedes an increase in IGF-1 expression” reports a dramatic increase in IL-1β mRNA at week 3 that was sustained through week 6. It does not specify that up-regulation began in the first week or increased gradually before week 3. (LLM, conf=0.85)

  Experimental — accuracy not yet measured

The inflammatory response has a beneficial role in repair processes after a demyelinating insult.

“again emphasizing a beneficial role of the inflammatory response in the repair processes after a demyelinating insult.”

• cites Arnett et al., 2003 sourceSupported

Differentiation of OPC and thus remyelination are dramatically reduced in the absence of IL-1β.

“In this study Mason and colleagues have shown that differentiation of OPC and thus, remyelination are dramatically reduced in absence of IL-1β”

• cites Mason et al., 2001 sourceSupported

Remyelination was slightly delayed in mice lacking LtβR.

“However, remyelination was slightly delayed in mice lacking LtβR (Plant et al., 2007).”

• cites Plant et al., 2007 sourceSupported

In the cuprizone model, LtβR is expressed by microglia.

“while LtβR by microglia (Plant et al., 2007).”

• cites Plant et al., 2007 sourceSupported

Several genes of the MHC-family were reduced in mice lacking TNF-α.

“In particular, several genes of the MHC-family were reduced in the mice lacking TNF-α (Arnett et al., 2003).”

• cites Arnett et al., 2003 sourceSupported

Surviving oligodendrocytes in IGF-1 over-expressing mice seem to retain the ability to remyelinate timely at week 5 regardless of remaining myelin debris.

“Moreover, these surviving oligodendrocytes even seem to retain the ability to remyelinate timely on week 5, regardless of remaining myelin debris (Mason et al., 2000b).”

• cites Mason et al., 2000b sourcePartly supported

  The Discussion (page unavailable) says that remyelination occurred at weeks 4 and 5 in IGF-1 transgenic mice and that surviving mature oligodendrocytes most likely contributed. The Early recovery section (page unavailable) reports substantial remyelination at week 5. Our copy does not establish that myelin debris remained or that remyelination occurred regardless of it. (LLM, conf=0.86)

  Experimental — accuracy not yet measured

IGF-1 has a highly protective role on oligodendrocytes.

“suggesting a highly protective role of IGF-1 on oligodendrocytes.”

• cites Mason et al., 2000b sourceSupported

In IGF-1 over-expressing mice, mature oligodendrocytes were numerously present in the corpus callosum during demyelination instead of being nearly completely depleted.

“Furthermore, instead of being nearly completely depleted, mature oligodendrocytes were numerously present in the CC of IGF-1 over-expressing mice during demyelination”

• cites Mason et al., 2000b sourceSupported

In conditional mouse mutants with Igf1r ablated exclusively in neurons and OPC of the cerebrum, reduced accumulation of OPC led to a decreased amount of newly generated oligodendrocytes.

“In conditional mouse mutants, in which the expression of the Igf1r gene was ablated exclusively in neurons and OPC of the cerebrum, there was a reduced accumulation of OPC, leading to a decreased amount of newly generated oligodendrocytes (Mason et al., 2003).”

• cites Mason et al., 2003 sourcePartly supported

  The sections on progenitor accumulation and mature oligodendrocyte regeneration report fewer progenitors and fewer regenerated oligodendrocytes in conditional mutants after cuprizone-induced demyelination. But the paper describes their spatial relationship as a correlation, not proof that reduced progenitor accumulation caused the decrease. The ablation section also reports low-level recombination in the cerebellum and testis, so deletion was not exclusively confined to neurons and OPCs of the cerebrum. (LLM, conf=0.86)

  Experimental — accuracy not yet measured

All four FGF receptors are highly regulated upon cuprizone treatment and during remyelination.

“A recent study of Zhou and colleagues showed that all four FGF receptors are highly regulated upon cuprizone treatment and during remyelination (Zhou et al., 2012).”

• cites Zhou et al., 2012 sourcePartly supported

  The Results section on FGF-family expression (page not provided) examines the cuprizone demyelination and recovery time course and identifies FGFR1 in a cluster of genes that increase during demyelination. It does not report that all four FGF receptors are highly regulated during treatment and remyelination; the Discussion's reference to multiple upregulated FGF-family members concerns ligands, not receptors. (LLM, conf=0.84)

  Experimental — accuracy not yet measured

Several growth factors such as FGF-2, CNTF, IGF-1, and GDNF are strongly regulated during cuprizone treatment and/or in the recovery phase.

“We found that several growth factors such as FGF-2, CNTF, IGF-1, and glial cell-derived neurotrophic factor (GDNF) are strongly regulated during cuprizone treatment and/or in the recovery phase.”

• cites Gudi et al., 2011 sourceSupported

Absence of FGF-2 leads to faster regeneration/differentiation of oligodendrocytes after cuprizone-induced demyelination.

“Taking advantage of FGF-2 −/− mice Armstrong et al. have shown that the absence of FGF-2 leads to a faster regeneration/differentiation of oligodendrocytes after cuprizone-induced demyelination (Armstrong et al., 2002).”

• cites Armstrong et al., 2002 sourceSupported

In IFN-γR−/− mice, cuprizone-induced microglia accumulation was initially diminished or simply delayed.

“In contrast, in IFN-γR −/− mice cuprizone-induced microglia accumulation was initially diminished or simply delayed (Mana et al., 2006)”

• cites Mana et al., 2006 sourceSupported

In mice that constantly over-expressed IGF-1 within the brain, microgliosis was more pronounced after 3 weeks of cuprizone diet than in wild-type mice.

“microgliosis was more pronounced in mice that constantly over-expressed IGF-1 within the brain after 3 weeks of cuprizone diet (Mason et al., 2000b).”

• cites Mason et al., 2000b sourceSupported

Depletion of iNOS exacerbated demyelination in the cuprizone model.

“Similar in the cuprizone model, a depletion of iNOS exacerbated demyelination (Arnett et al., 2002)”

• cites Arnett et al., 2002 sourceSupported

The sequential delivery result indicates the complexity of growth factor fine tuning and interplay.

“indicating the complexity of growth factor fine tuning and interplay.”

• cites Sabo et al., 2013 sourceSupported

Infusion of Noggin, an antagonist of the BMP4-pathway, promoted maturation of oligodendrocytes and potentiated remyelination in the corpus callosum after cuprizone withdrawal.

“Conversely, infusion of Noggin, an antagonist of the BMP4-pathway, promoted maturation of oligodendrocytes and potentiated remyelination in the CC after cuprizone withdrawal (Sabo et al., 2011).”

• cites Sabo et al., 2011 sourceSupported

Bone morphogenic protein (BMP) plays an important role in modulating oligodendrogliogenesis and remyelination.

“The results of the study by Sabo et al. indicated an important role for bone morphogenic protein (BMP) in modulating oligodendrogliogenesis and remyelination (Sabo et al., 2011).”

• cites Sabo et al., 2011 sourceSupported

The BMP pathway was activated in astrocytes and Olig2-positive cells during cuprizone-induced demyelination.

“The BMP-pathway was also activated in astrocytes and Olig2-positive cells during cuprizone-induced demyelination (Sabo et al., 2011).”

• cites Sabo et al., 2011 sourceSupported

Sequential delivery of BMP4 between weeks 4 and 5 followed by Noggin infusion for the following week did not improve remyelination.

“However, the sequential delivery of BMP4 between weeks 4 and 5 followed by Noggin infusion for the following week did not improve remyelination (Sabo et al., 2013)”

• cites Sabo et al., 2013 sourceSupported

Intraventricular delivery of BMP4 for 7-14 days transiently increased proliferation predominantly of OPC and to a lower degree of astrocytes and microglia.

“An intraventricular delivery of BMP4 for 7–14 days (4–5 or 4–6 week of cuprizone diet) transiently increased the proliferation predominantly of OPC and to a lower degree of astrocytes and microglia.”

• cites Sabo et al., 2011 sourcePartly supported

  The short-term infusion Results report increased proliferation of OPCs, microglia and astrocytes after 5 days of BMP4 infusion; the modulation Results also report increased proliferating oligodendroglial cells after 14 days. The Discussion describes OPC proliferation as predominant and notes that oligodendroglial numbers fell after a week of recovery. The stated 7-day delivery period is not supported: the shorter infusion lasted 5 days. Page numbers were not provided in our copy. (LLM, conf=0.87)

  Experimental — accuracy not yet measured

In our own study, LIF mRNA expression was up-regulated very early mainly during the first 3 weeks of cuprizone administration in both corpus callosum and cortex, thereafter decreasing to normal levels in the recovery phase after toxin withdrawal.

“In our own study we were able to show that LIF mRNA expression was up-regulated very early mainly during the first 3 weeks of cuprizone administration in both CC and cortex thereafter decreasing to normal levels in the recovery phase after toxin withdrawal (Gudi et al., 2011).”

• cites Gudi et al., 2011 sourcePartly supported

  Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

  Experimental — accuracy not yet measured

A TNF-α-mediated mechanism of remyelination via astrocytic CXCL12 is suggested.

“suggesting a TNF-α-mediated mechanism of remyelination via astrocytic CXCL12 (Patel et al., 2012).”

• cites Patel et al., 2012 sourceSupported

Lentiviral gene delivery of CXCL12 into TNFR2−/− mice could rescue this effect.

“The lentiviral-gene delivery of CXCL12 into TNFR2 −/− mice could rescue this effect”

• cites Patel et al., 2012 sourceSupported

Using the cuprizone model, the authors could demonstrate an important crosstalk between astrocytes and microglia.

“Using the cuprizone model we could demonstrate that there is an important crosstalk between astrocytes and microglia.”

Differentiated oligodendrocytes but not OPC are affected by cuprizone in vitro.

“Recently we have shown that especially differentiated oligodendrocytes but not OPC are affected by cuprizone in vitro (Benardais et al., 2013).”

• cites Benardais et al., 2013 sourceNot checked — no full text of the source

CXCL10 mRNA expression was reduced in astrocyte-depleted mice.

“Our studies suggested that this process may be regulated by the chemokine CXCL10 since CXCL10 mRNA expression was reduced in the astrocyte-depleted mice”

• cites Skripuletz et al., 2013 sourceNot checked — no full text of the source

Treatment of astrocyte cultures with LPS, IL-1β, or TNF-α led to an enhancement of CXCL10 production in vitro.

“and the treatment of astrocyte cultures with LPS, IL-1β, or TNF-α led to an enhancement of CXCL10 production in vitro (Skripuletz et al., 2013).”

• cites Skripuletz et al., 2013 sourceNot checked — no full text of the source

Partial ablation of astrocytes in mice challenged for 3 weeks with cuprizone did not reveal any difference in CCL2 and CCL3 expression.

“Interestingly, a partial ablation of astrocytes in mice challenged for 3 weeks with cuprizone did not reveal any difference in CCL2 and CCL3 expression”

• cites Skripuletz et al., 2013 sourceNot checked — no full text of the source

We detected up-regulated expression of CCL2 and CCL3 upon cuprizone treatment.

“In line with other studies (McMahon et al., 2001; Buschmann et al., 2012) we could also detect an up-regulated expression of CCL2 and CCL3 upon cuprizone treatment (Skripuletz et al., 2013).”

• cites Skripuletz et al., 2013 sourceNot checked — no full text of the source

The activation of astrocytes and microglia in the cuprizone model shows regional heterogeneity between different white and gray matter regions.

“Cuprizone induces apoptosis of mature oligodendrocytes that leads to a robust demyelination and profound activation of both astrocytes and microglia with regional heterogeneity between different white and gray matter regions.”

The dose of cuprizone is one of the most important factors to induce demyelination in the murine CNS.

“The dose of cuprizone is one of the most important factors to induce demyelination in the murine CNS.”

Remyelination rapidly progresses after termination of the cuprizone diet (acute demyelination).

“Remyelination rapidly progresses after termination of the cuprizone diet (acute demyelination, Figure 1).”

Cuprizone induces apoptosis of mature oligodendrocytes.

“Cuprizone induces apoptosis of mature oligodendrocytes that leads to a robust demyelination and profound activation of both astrocytes and microglia with regional heterogeneity between different white and gray matter regions.”

The local cellular microenvironment can promote or prevent deleterious effects of cuprizone and demyelination and remyelination.

“suggesting that the local cellular microenvironment can promote or prevent deleterious effects of cuprizone and demyelination and remyelination.”

Cuprizone directly or indirectly impairs a variety of essential cell functions.

“In the light of all these evidences it is obvious that cuprizone directly or indirectly impairs a variety of essential cell functions.”

Toxic demyelination is more appropriate to study remyelination than EAE.

“Although EAE is probably the most commonly used model that reflects the autoimmune origin of MS, toxic demyelination is more appropriate to study remyelination.”

Phagocytosis and removal of damaged myelin is one of the major roles of microglia in the cuprizone model.

“Phagocytosis and removal of damaged myelin seems to be one of the major roles of microglia in this model and it is well known that removal of myelin debris is a prerequisite of successful remyelination.”

• AssumptionRests on an assumption: Removal of myelin debris is a prerequisite of successful remyelination.

The cuprizone model is not suitable to study autoimmune mediated demyelination.

“Although not suitable to study autoimmune mediated demyelination, this model is extremely helpful to elucidate basic cellular and molecular mechanisms during de- and particularly remyelination independently of interactions with peripheral immune cells.”

Cuprizone-induced demyelination is accompanied by profound activation of both astrocytes and microglia.

“Cuprizone induces apoptosis of mature oligodendrocytes that leads to a robust demyelination and profound activation of both astrocytes and microglia with regional heterogeneity between different white and gray matter regions.”

Cuprizone is a copper chelating reagent that, when supplemented to normal rodent chow, directly or indirectly causes oligodendroglial cell death with subsequent demyelination.

“Cuprizone [bis–cyclohexanone-oxaldihydrazone] is a copper chelating reagent, which supplemented to normal rodent chow, directly or indirectly causes oligodendroglial cell death with subsequent demyelination.”

The cuprizone model is suitable to study basic glial reactions and interactions during de- and remyelination in the absence of primarily immune-mediated mechanisms.

“Thus, the cuprizone model is a suitable tool to study basic glial reactions and interactions during de- and re-myelination in absence of primarily immune-mediated mechanisms.”

When cuprizone is fed continuously, remyelination is abortive and demyelination persists until the end of the diet (chronic demyelination).

“When cuprizone is fed continuously remyelination is abortive and demyelination persists till the end of the diet (chronic demyelination).”

Copper administration (100 ppm) synchronously to cuprizone administration (0.5%) did not reduce the toxic effects.

“However, copper administration (100 ppm) synchronously to cuprizone administration (0.5%) did not reduce the toxic effects (Carlton, 1967).”

• cites Carlton, 1967 sourceNot checked — no full text of the source

Axonal damage and glial response accompanying demyelination are more severe and prolonged in aged (6-7 months) as compared to young (8-10 weeks) mice.

“Axonal damage and glial response accompanying demyelination were more severe and prolonged in aged (6–7 months) as compared to young (8–10 weeks) mice (Irvine and Blakemore, 2006).”

• cites Irvine and Blakemore, 2006 sourceNot checked — no full text of the source

0.2% (w/w) cuprizone was established to induce highly reproducible and extensive demyelination without detrimental systemic effects in 8-10 weeks old mice.

“Thus, 0.2% (w/w) cuprizone was established to induce highly reproducible and extensive demyelination without detrimental systemic effects in 8–10 weeks old mice.”

• cites Hiremath et al., 1998 sourceNot checked — no full text of the source

p75NTR does not play a major role in the induction of apoptosis in the cuprizone model.

“Since p75NTR −/− mice did not show any alteration regarding the course of de- and remyelination or glial reactions it is obvious that p75NTR does not play a major role in the induction of apoptosis in the cuprizone model.”

• cites Copray et al., 2005 sourceNot checked — no full text of the source

Mitochondrial disturbances seem to be the key factor of oligodendroglial apoptosis.

“However, mitochondrial disturbances seem to be the key factor of oligodendroglial apoptosis, since enlarged “giant” mitochondria were detected in the liver and brain of cuprizone-treated mice (Suzuki, 1969; Hemm et al., 1971; Komoly et al., 1987).”

• cites Suzuki, 1969Not matched

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

• cites Hemm et al., 1971 sourceNot checked — no full text of the source
• cites Komoly et al., 1987 sourceNot checked — no full text of the source

• AssumptionRests on an assumption: A regular function of mitochondria is essential for oligodendroglial survival.

Cuprizone-induced oligodendroglial cell death followed by myelin clearance is an artificial event directly or indirectly caused by the toxin.

“However, it always has to be kept in mind, that cuprizone-induced oligodendroglial cell death followed by myelin clearance is an artificial event directly or indirectly caused by this toxin.”

Cuprizone-induced apoptosis of mature oligodendrocytes leads to robust demyelination.

“Cuprizone induces apoptosis of mature oligodendrocytes that leads to a robust demyelination and profound activation of both astrocytes and microglia with regional heterogeneity between different white and gray matter regions.”

The cuprizone model is helpful to elucidate basic cellular and molecular mechanisms during de- and particularly remyelination independently of interactions with peripheral immune cells.

“Although not suitable to study autoimmune mediated demyelination, this model is extremely helpful to elucidate basic cellular and molecular mechanisms during de- and particularly remyelination independently of interactions with peripheral immune cells.”

Demyelination may also be detected in other brain regions such as hippocampus, basal ganglia, and cerebellum.

“Furthermore, demyelination may also be detected in other brain regions such as hippocampus, basal ganglia, and cerebellum (Koutsoudaki et al., 2009; Pott et al., 2009; Skripuletz et al., 2010a).”

• cites Koutsoudaki et al., 2009 sourceNot checked — no full text of the source
• cites Pott et al., 2009 sourceNot checked — no full text of the source
• cites Skripuletz et al., 2010a sourceNot checked — no full text of the source

Once demyelination is complete, new oligodendrocytes generated from the pool of oligodendrocyte progenitors (OPC) begin to form new myelin sheaths.

“Once demyelination is complete new oligodendrocytes, generated from the pool of oligodendrocyte progenitors (OPC), begin to form new myelin sheaths.”

Depletion of macrophages via clodronate-liposomes prior/after lysolecithin-induced demyelination delays OPC recruitment.

“Kotter and colleagues, who demonstrated a delayed OPC recruitment after the depletion of macrophages via exposure of mice to clodronate-liposomes prior/after lysolecithin-induced demyelination.”

• cites Kotter et al., 2001 sourceNot checked — no full text of the source
• cites Kotter et al., 2005 sourceNot checked — no full text of the source

In the acute cuprizone model, activated microglia appear already at the first 2 weeks even before demyelination can be detected by histology and immunohistochemistry.

“In the acute cuprizone model activated microglia appear already at the first 2 weeks even before demyelination can be detected by histology and immunohistochemistry (Hiremath et al., 1998) (Figure 2).”

• cites Hiremath et al., 1998 sourceNot checked — no full text of the source

In the case of continued cuprizone feeding until week 6, newly generated oligodendrocytes are damaged again.

“It seems that in the case of continued cuprizone feeding until week 6 newly generated oligodendrocytes are damaged again.”

During demyelination in the cuprizone model, the most representative type of microglia expressed CD11b+/CD45low and displayed high ex vivo phagocytic activity accompanied by up-regulation of Trem2b, FcγR II/III, CD36, and Tim-3.

“The most representative type of microglia during demyelination expressed CD11b+/CD45low (CD, cluster of differentiation) and displayed a high ex vivo phagocytic activity accompanied by up-regulation of several phagocytic receptors such as Trem2b, FcγR II/III, CD36, and Tim-3 (Voss et al., 2012)”

• cites Voss et al., 2012Not matched

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

The delayed OPC recruitment after macrophage depletion is linked to an altered growth factor expression in macrophage-depleted animals.

“The authors linked this phenomenon to an altered growth factor expression in macrophage-depleted animals (Kotter et al., 2001, 2005).”

• cites Kotter et al., 2001 sourceNot checked — no full text of the source
• cites Kotter et al., 2005 sourceNot checked — no full text of the source

Phagocytosis is one of the most prominent features of microglia in the cuprizone model.

“suggesting that phagocytosis is one of the most prominent features of microglia in the cuprizone model”

MHC class II expression was significantly increased at the maximum of demyelination (week 5) in both the corpus callosum and the cortex.

“The expression of MHC class II was significantly increased at the maximum of demyelination (week 5) in both the CC and the cortex (Voss et al., 2012).”

• cites Voss et al., 2012Not matched

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

After 3 weeks, activated microglia are numerously present in the corpus callosum, cortex, and hippocampus.

“After 3 weeks activated microglia are numerously present in the CC, cortex, and hippocampus.”

Remyelination was accelerated in St8siaIV knockout mice.

“and remyelination was accelerated in ST8 alpha-N-Acetyl-Neuraminide alpha-2,8-Sialyltransferase 4 (St8siaIV, the polysialyltransferase responsible for PSA synthesis) knockout mice (Koutsoudaki et al., 2010), suggesting that these molecular mechanisms are indeed involved in remyelination.”

• cites Koutsoudaki et al., 2010 sourceNot checked — no full text of the source

TNF-α production was strongly increased during primary demyelination in both white and gray matter microglia.

“TNF-α production was strongly increased during primary demyelination in both white and gray matter microglia.”

• cites Voss et al., 2012Not matched

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

The extent of microglial accumulation during cuprizone-induced demyelination is not uniform.

“The extent of microglial accumulation during cuprizone-induced demyelination is not uniform as well.”

Repair mechanisms start very early even before demyelination can be detected immunohistochemically.

“These repair mechanisms start very early even before demyelination can be detected immunohistochemically.”

Remyelination capacity is clearly reduced after withdrawal of cuprizone.

“However, the remyelination capacity was clearly reduced after the withdrawal of cuprizone (Ludwin, 1980; Lindner et al., 2009).”

• cites Ludwin, 1980Not checked — no full text of the source
• cites Lindner et al., 2009 sourceNot checked — no full text of the source

Cerebellar gray and white matter shows severe demyelination after 12 weeks of cuprizone feeding.

“Cerebellar gray and white matter shows severe demyelination after 12 weeks of cuprizone feeding (Skripuletz et al., 2010a).”

• cites Skripuletz et al., 2010a sourceNot checked — no full text of the source

These molecular mechanisms (LINGO-1, PSA-NCAM) are involved in remyelination.

“suggesting that these molecular mechanisms are indeed involved in remyelination.”

• cites Mi et al., 2009Not matched

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

• cites Koutsoudaki et al., 2010 sourceNot checked — no full text of the source

Following cuprizone-induced demyelination, the peak of microglial activation tightly correlates with a massive accumulation of OPC.

“Conspicuously, following cuprizone-induced demyelination the peak of microglial activation tightly correlates with a massive accumulation of OPC.”

Degradation/re-expression of different myelin proteins follows individual temporal patterns.

“It is important to mention that degradation/re-expression of different myelin proteins (at least in the CC and as depicted by immunohistochemistry) follows individual temporal pattern (Gudi et al., 2009).”

• cites Gudi et al., 2009 sourceNot checked — no full text of the source

In the next 2-3 weeks, highly activated and proliferating microglia clear myelin debris.

“In the next 2–3 weeks highly activated and proliferating microglia clear myelin debris.”

TGF-β, IFN-γ, IL-12, and IL-10 were not regulated during primary demyelination.

“In contrast, TGF-β, IFN-γ, IL-12, and IL-10 were not regulated (Voss et al., 2012).”

• cites Voss et al., 2012Not matched

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

Cuprizone ingestion in mice led to enlargement and hyperplasia of astroglia in brain regions that showed signs of cuprizone-induced demyelination.

“Already in the 1960s Carlton reported that cuprizone ingestion in mice led to enlargement and hyperplasia of astroglia in brain regions that showed signs of cuprizone-induced demyelination”

• cites Carlton, 1967 sourceNot checked — no full text of the source

Astrocytes show significantly lower gene and protein expression of GFAP after chronic demyelination compared to acute demyelination.

“Since astrocytes show significantly lower gene and protein expression of GFAP after chronic demyelination compared to acute demyelination”

• cites Ludwin, 1980Not checked — no full text of the source
• cites Kipp et al., 2011b sourceNot checked — no full text of the source

Ablation of astrocytes during cuprizone-induced demyelination resulted in diminished activation and invasion of microglia into the demyelinated lesion.

“but resulted in a diminished activation and invasion of microglia into the demyelinated lesion.”

• cites Skripuletz et al., 2013 sourceNot checked — no full text of the source

Astrocytes display signs of proliferation during the course of acute demyelination.

“Concomitantly, astrocytes display signs of proliferation during the course of acute demyelination (Hiremath et al., 1998; Gudi et al., 2009).”

• cites Hiremath et al., 1998 sourceNot checked — no full text of the source
• cites Gudi et al., 2009 sourceNot checked — no full text of the source

The number of astrocytes is not significantly increased until 3 weeks of cuprizone treatment, simultaneously with first signs of apparent demyelination.

“The number of astrocytes is not significantly increased until 3 weeks of cuprizone treatment, simultaneously with first signs of apparent demyelination.”

Astrocytosis preceded loss of myelin in cuprizone-treated mice.

“and that astrocytosis preceded loss of myelin (Carlton, 1967)”

• cites Carlton, 1967 sourceNot checked — no full text of the source

FABP7 expression in activated astrocytes has a potential beneficial role for remyelination.

“indicating a potential beneficial role of FABP7 expression in activated astrocytes for remyelination.”

The co-stimulatory capacity of microglia in the cuprizone model was not sufficient to activate T cells.

“suggesting that the co-stimulatory capacity of microglia in the cuprizone model was not sufficient to activate T cells”

Expression of FABP7 in astrocytes correlated with remyelination of lesions in EAE and MS.

“Interestingly, the expression of FABP7 in astrocytes also correlated with remyelination of lesions in EAE and MS”

Astrocytes are responsible for the recruitment of microglia.

“It was concluded, that astrocytes are responsible for the recruitment of microglia.”

• cites Skripuletz et al., 2013 sourceNot checked — no full text of the source

5-7% of CD11b+/CD45high cells were present in the corpus callosum at week 5 and 6, even 1 week after cuprizone diet cessation.

“Our own study revealed that 5–7% of CD11b+/CD45high cells were present in the CC at week 5 and 6, even 1 week after cuprizone diet cessation (Voss et al., 2012).”

• cites Voss et al., 2012Not matched

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

FABP7 induced the expression of various growth factors in vitro, including FGF2, PDGFα, and osteopontin.

“and induced the expression of various growth factors in vitro [FGF2, PDGFα, and osteopontin (OPN)]”

The activation status of astrocytes appears to be higher after acute demyelination than after chronic demyelination.

“the activation status of astrocytes appears to be higher after acute demyelination (Ludwin, 1980; Kipp et al., 2011b)”

• cites Ludwin, 1980Not checked — no full text of the source
• cites Kipp et al., 2011b sourceNot checked — no full text of the source

Macrophages constituted 1-4% of the RCA-1+ population at week 5-6 of cuprizone exposure.

“macrophages constituted 1–4% of the RCA-1+ population at week 5–6 of cuprizone exposure (McMahon et al., 2002)”

• cites McMahon et al., 2002 sourceNot checked — no full text of the source

CD200R was rather up-regulated during early demyelination.

“CD200R was rather up-regulated during early demyelination (Voss et al., 2012).”

• cites Voss et al., 2012Not matched

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

Expression of TIMP was increased during the demyelination peak between weeks 4.5 and 5.

“In contrast, the expression of endogenous antagonists of metalloproteinases (TIMP) was increased during the demyelination peak between weeks 4.5 and 5.”

• cites Skuljec et al., 2011 sourceNot checked — no full text of the source

Beneficial effects of TNF-α on proliferation of OPC and subsequent remyelination are promoted through the TNFR2 pathway.

“suggesting that beneficial effects of TNF-α on proliferation of OPC and subsequent remyelination are promoted through the TNFR2 pathway (Arnett et al., 2001).”

• cites Arnett et al., 2001 sourceNot checked — no full text of the source

MMP12 was additionally up-regulated during the demyelination phase.

“MMP12 was additionally up-regulated during the demyelination phase”

• cites Skuljec et al., 2011 sourceNot checked — no full text of the source

In the cuprizone model, Lt-α is expressed primarily by astroglia.

“In the cuprizone model, Lt-α is expressed primarily by astroglia (Plant et al., 2005)”

• cites Plant et al., 2005 sourceNot checked — no full text of the source

MMP3 was localized exclusively in activated astrocytes.

“MMP3 was localized exclusively in activated astrocytes”

• cites Skuljec et al., 2011 sourceNot checked — no full text of the source

TNFR2 but not TNFR1 was gradually up-regulated during de- and remyelination.

“In this study TNFR2 but not TNFR1 has been shown to be gradually up-regulated during de- and remyelination (Arnett et al., 2001).”

• cites Arnett et al., 2001 sourceNot checked — no full text of the source

There is increasing evidence that astrocytes are key players in complex interactions with OPC, mature oligodendrocytes, and microglia supporting remyelination at least in the cuprizone model.

“There is increasing evidence that astrocytes are key players in complex interactions with OPC, mature oligodendrocytes, and microglia supporting remyelination at least in the cuprizone model.”

MMP have a regulatory role in tissue regeneration.

“arguing for a regulatory role of MMP in tissue regeneration (Skuljec et al., 2011)”

• cites Skuljec et al., 2011 sourceNot checked — no full text of the source

An adequate and controlled inflammatory response is required for successful myelin regeneration, promoting clearance of myelin debris and stimulating proliferation/regeneration of myelin-forming oligodendrocytes.

“However, a growing body of evidence corroborates the assumption that an adequate and controlled inflammatory response is required for a successful myelin regeneration promoting the clearance of myelin debris and stimulating proliferation/regeneration of myelin-forming oligodendrocytes (Diemel et al., 1998; Robinson and Miller, 1999; Arnett et al., 2001; Kotter et al., 2001, 2005, 2006; Setzu et al”

• cites Diemel et al., 1998 sourceNot checked — no full text of the source
• cites Arnett et al., 2001 sourceNot checked — no full text of the source
• cites Kotter et al., 2001 sourceNot checked — no full text of the source

Significant changes in the expression of several MMP occur especially during the remyelination phase.

“Previously, our group could show significant changes in the expression of several MMP, especially during the remyelination phase, arguing for a regulatory role of MMP in tissue regeneration (Skuljec et al., 2011).”

• cites Skuljec et al., 2011 sourceNot checked — no full text of the source

The course of remyelination was not influenced by the Lt-α mutation.

“The course of remyelination was not influenced by this mutation.”

• cites Plant et al., 2005 sourceNot checked — no full text of the source

The source of TIMP1 in the CNS is linked to astrocytes.

“whereas the source of TIMP1 in the CNS is linked to astrocytes (Gardner and Ghorpade, 2003).”

• cites Gardner and Ghorpade, 2003 sourceNot checked — no full text of the source

OPN was up-regulated in MS lesions and in several experimental animal models for demyelination including the cuprizone model.

“Previously, OPN was shown to be up-regulated in MS lesions and in several experimental animal models for demyelination including the cuprizone model (Chabas et al., 2001; Selvaraju et al., 2004; Zhao et al., 2008).”

• cites Chabas et al., 2001 sourceNot checked — no full text of the source
• cites Selvaraju et al., 2004 sourceNot checked — no full text of the source
• cites Zhao et al., 2008 sourceNot checked — no full text of the source

MMP7, -9, -11, -13, and -15 were either not regulated or even down-regulated during myelin clearance in the corpus callosum.

“however, MMP7, -9, -11, -13, -15 were either not regulated or even down-regulated during myelin clearance in the CC.”

• cites Skuljec et al., 2011 sourceNot checked — no full text of the source

Depletion of astrocytes resulted in diminished numbers of mature oligodendrocytes during remyelination.

“In addition, the depletion of astrocytes resulted in diminished numbers of mature oligodendrocytes during remyelination (Skripuletz et al., 2013).”

• cites Skripuletz et al., 2013 sourceNot checked — no full text of the source

TNFR2−/− mice displayed diminished/delayed regeneration of myelin.

“Furthermore, similar to TNF-α-deficient mice TNFR2 −/− mice displayed diminished/delayed regeneration of myelin”

• cites Arnett et al., 2001 sourceNot checked — no full text of the source

TIMP2 was expressed by microglia.

“TIMP2 was found to be expressed by microglia (Skuljec et al., 2011)”

• cites Skuljec et al., 2011 sourceNot checked — no full text of the source

Expression of MMP11, MMP12, and MMP3 was clearly increased during remyelination.

“In particular, the expression of MMP11, MMP12, and MMP3 was clearly increased during remyelination.”

• cites Skuljec et al., 2011 sourceNot checked — no full text of the source

In the cuprizone model, deleterious effects of MMP and inflammatory processes themselves are tightly controlled by TIMP.

“It seems, however, that in the cuprizone model deleterious effects of MMP and inflammatory processes themselves are tightly controlled by TIMP.”

The effects of IFN-γ and other pro-inflammatory molecules, whether harmful or helpful, are dependent on their quantitative and temporal expression pattern.

“In conclusion, these conflicting results may allow the assumption that the effects of IFN-γ and other pro-inflammatory molecules, whether harmful or helpful, are dependent on their quantitative and temporal expression pattern.”

PDGFα is a potent mitogen for OPC.

“Being a potent mitogen for OPC PDGFα is one of the prominent compounds of the culture medium of primary cortical OPC derived from new-borns or embryos as well as immortalized OPC in vitro (Noble et al., 1988; Bansal et al., 1996).”

• cites Noble et al., 1988 sourceNot checked — no full text of the source
• cites Bansal et al., 1996 sourceNot checked — no full text of the source

Differentiation of OPC was not altered in PDGFαR+/− mice.

“Differentiation of OPC was, however, not altered in PDGFαR +/− mice (Murtie et al., 2005b).”

• cites Murtie et al., 2005b sourceNot checked — no full text of the source

Upon cuprizone treatment, expression of OPN was increased on the peak of demyelination and during early remyelination in activated astrocytes and microglia.

“Upon cuprizone treatment the expression of OPN was increased on the peak of demyelination and during early remyelination in activated astrocytes and microglia.”

PDGFαR-signaling has an important role in OPC proliferation.

“arguing for an important role of PDGFαR-signaling on OPC proliferation.”

• cites Murtie et al., 2005b sourceNot checked — no full text of the source

IGF-1 has a positive effect on mature oligodendrocyte survival in vitro.

“The positive effect of IGF-1 on mature oligodendrocyte survival was also observed in vitro (Barres et al., 1992, 1993; Ye and D'Ercole, 1999).”

• cites Barres et al., 1992, 1993; Ye and D'Ercole, 1999Not matched

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

IGF-1 mRNA expression was observed in activated microglia.

“In our own studies we could confirm this finding; however, additionally we observed IGF-1 mRNA expression in activated microglia (Voss et al., 2012).”

• cites Voss et al., 2012Not matched

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

OPC density seems not to be a rate-limiting factor for a successful remyelination.

“Since there was no significant enhancement of remyelination in the lysolecithin model the authors concluded, that the OPC density seems not to be a rate-limiting factor for a successful remyelination (Woodruff et al., 2004).”

• cites Woodruff et al., 2004 sourceNot checked — no full text of the source

Impaired oligodendrocyte repopulation in PDGFαR heterozygous knockout mice is caused by a reduced proliferation capacity and overall density of OPC.

“Another study showed an impaired oligodendrocyte repopulation in PDGFαR heterozygous knockout mice, caused by a reduced proliferation capacity and overall density of OPC arguing for an important role of PDGFαR-signaling on OPC proliferation.”

• cites Murtie et al., 2005b sourceNot checked — no full text of the source

Microgliosis was more pronounced in mice that constantly over-expressed IGF-1 within the brain after 3 weeks of cuprizone diet.

“Interestingly, microgliosis was more pronounced in mice that constantly over-expressed IGF-1 within the brain after 3 weeks of cuprizone diet (Mason et al.,”

• cites Mason et al.Not matched

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

LPS, IL-1β, and TNF-α induce CCL2 secretion by astrocytes, but not microglia, in vitro.

“LPS, IL-1β, and TNF-α-induced CCL2 secretion by astrocytes, but not microglia in vitro (Hayashi et al., 1995).”

• cites Hayashi et al., 1995 sourceNot checked — no full text of the source

BMP-signaling plays an important role in demyelinating events.

“suggesting an important role for BMP-signaling in demyelinating events.”

• cites Ara et al., 2008 sourceNot checked — no full text of the source

Astrocyte-derived factors mediate attraction of microglia.

“arguing for astrocyte-derived factors that mediate attraction of microglia.”

• cites Skripuletz et al., 2013 sourceNot checked — no full text of the source

In vivo, BMP4 expression was elevated in OPC within demyelinated lesions induced by ethidium bromide.

“In vivo, the expression of BMP4 was elevated in OPC within demyelinated lesions induced by ethidium bromide (Zhao et al., 2005).”

• cites Zhao et al., 2005 sourceNot checked — no full text of the source

In cuprizone-induced demyelination, CCL2 expression was a transient phenomenon, being significantly up-regulated particularly during the first week of cuprizone exposure.

“In cuprizone-induced demyelination CCL2 expression was a transient phenomenon (McMahon et al., 2001; Buschmann et al., 2012) being significantly up-regulated particularly during the first week of cuprizone exposure.”

• cites McMahon et al., 2001; Buschmann et al., 2012Not matched

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

This process may be regulated by the chemokine CXCL10.

“Our studies suggested that this process may be regulated by the chemokine CXCL10”

• cites Skripuletz et al., 2013 sourceNot checked — no full text of the source

CCL2 and CCL3 are not astrocyte-derived at least at this time point.

“suggesting that these cytokines are not astrocyte-derived at least at this time point (Skripuletz et al., 2013).”

• cites Skripuletz et al., 2013 sourceNot checked — no full text of the source

Upon cuprizone-induced demyelination, CCL3 mRNA expression was initiated already after 2 days and then gradually increased until week 4.

“Upon cuprizone-induced demyelination mRNA expression of chemokine CCL3 was initiated already after 2 days and then gradually increased until week 4 (McMahon et al., 2001; Buschmann et al., 2012).”

• cites McMahon et al., 2001; Buschmann et al., 2012Not matched

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

In wild-type mice, LIF complementation during the recovery phase did not further enhance remyelination.

“However, remyelination was not further enhanced if wt mice were complemented with LIF during the recovery phase (Marriott et al., 2008).”

• cites Marriott et al., 2008 sourceNot checked — no full text of the source

CNTF and LIF can prevent oligodendrocyte death under pro-inflammatory conditions in vitro.

“and can prevent oligodendrocyte death under pro-inflammatory conditions in vitro (Louis et al., 1993; Vartanian et al., 1995).”

• cites Louis et al., 1993; Vartanian et al., 1995Not matched

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

In LIF-deficient mice, oligodendrocyte replenishment, which includes OPC proliferation and differentiation, seemed not to be significantly compromised.

“Remarkably, the oligodendrocyte replenishment, which includes both OPC proliferation and differentiation, seemed not to be significantly compromised in these transgenic mice”

• cites Marriott et al., 2008 sourceNot checked — no full text of the source

CCL2 induces chemotaxis of microglia.

“Additionally, this study showed that CCL2 induces chemotaxis of microglia.”

• cites Hayashi et al., 1995 sourceNot checked — no full text of the source

In EAE, BMP4 was up-regulated upon demyelination.

“Similarly, in EAE BMP4 was up-regulated upon demyelination (Ara et al., 2008)”

• cites Ara et al., 2008 sourceNot checked — no full text of the source

The assessment of remyelination is complicated in EAE and in virus-mediated models due to concurrently occurring de- and remyelination.

“The assessment of remyelination is complicated in EAE and in virus mediated models due to concurrently occurring de- and remyelination.”

• cites Table 1Not matched

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

Another drawback of autoimmune-induced demyelination is the unpredictable localization of lesions that classically occur in the spinal cord.

“Another drawback of autoimmune-induced demyelination is the unpredictable localization of lesions that classically occur in the spinal cord.”

• cites Table 1Not matched

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

Similar to other toxin-induced demyelination models, lesion induction in the cuprizone model is probably not relevant to MS.

“Thus, similar to other toxin-induced demyelination models, lesion induction is probably not relevant to MS”

Activation of the CXCR4 cascade in OPC leads to migration, proliferation, and differentiation of these cells.

“Activation of the CXCR4 cascade in OPC leads to migration, proliferation, and differentiation of these cells (Dziembowska et al., 2005; Kadi et al., 2006; Maysami et al., 2006).”

• cites Dziembowska et al., 2005; Kadi et al., 2006; Maysami et al., 2006Not matched

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

The cellular source of CXCL12 within the corpus callosum of cuprizone-treated mice includes both GFAP-positive astrocytes and CD11b-positive microglia.

“The cellular source of CXCL12 within the CC of cuprizone-treated mice includes both GFAP-positive astrocytes and CD11b-positive microglia.”

• cites Patel et al., 2010 sourceNot checked — no full text of the source

In the adult CNS, CXCL12 orchestrates neurotransmission, neurotoxicity and neuroglial interactions.

“In the adult CNS, CXCL12 orchestrates neurotransmission, neurotoxicity and neuroglial interactions (Lazarini et al., 2003).”

• cites Lazarini et al., 2003 sourceNot checked — no full text of the source

Toxic models are commonly used to study remyelination since their kinetics are well predictable and the lesion site is known.

“Toxic models are commonly used to study remyelination since their kinetics are well predictable and the lesion site is known.”

• cites Table 1Not matched

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

The cuprizone model becomes increasingly attractive to study the underlying pathophysiological mechanisms of de- and remyelination to uncover regional differences.

“the cuprizone model becomes increasingly attractive to study the underlying pathophysiological mechanisms of de- and remyelination to uncover regional differences (Gudi et al., 2009; Pott et al., 2009; Schmidt et al., 2013).”

• cites Gudi et al., 2009; Pott et al., 2009; Schmidt et al., 2013Not matched

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

Complete demyelination of the corpus callosum occurs at week 5 of cuprizone feeding.

“However, it was already described in the early work by the group of Matsushima and confirmed by others that complete demyelination of the CC occurs at week 5 of cuprizone feeding.”

Remyelination is fast and robust after acute demyelination (cuprizone feeding for 5 weeks).

“Remyelination is fast and robust after acute demyelination (cuprizone feeding for 5 weeks).”

Known immunosuppressive therapeutics that are quite effective in relapsing-remitting MS extend limited beneficial effects during late stages of secondary-progressive and primary-progressive MS subtypes.

“Moreover, known immunosuppressive therapeutics that are quite effective in relapsing-remitting MS (RRMS) extend limited beneficial effects during late stages of secondary-progressive (SPMS) and primary-progressive (PPMS) MS subtypes (Bradl and Lassmann, 2009).”

• cites Bradl and Lassmann, 2009 sourceNot checked — no full text of the source

Another plus of toxic models is a clear read-out of remyelination since significant improvements of remyelination can be gradually reflected by functional recovery of the animals.

“Another plus of these models is a clear read-out of remyelination since significant improvements of remyelination can be gradually reflected by functional recovery of the animals.”

• cites Table 1Not matched

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

The cellular composition seems to differ between white and gray matter MS lesions.

“since recent studies have shown that the de- and remyelination extend as well the cellular composition seems to differ between white and gray matter MS lesions (Bo et al., 2003; Albert et al., 2007; Van Horssen et al., 2007)”

• cites Bo et al., 2003; Albert et al., 2007; Van Horssen et al., 2007Not matched

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

Even 2-3 weeks of cuprizone ingestion is sufficient to induce glial responses and de- and remyelination pattern similar to that described for 5-6 week treatment.

“A recent study provided insights that even 2–3 weeks of cuprizone ingestion is sufficient to induce glial responses and de- and remyelination pattern similar to that described for 5–6 week treatment (Doan et al., 2013).”

• cites Doan et al., 2013 sourceNot checked — no full text of the source

In toxic animal models such as lysolecithin and ethidium bromide models, a focal myelin loss is induced by stereotactic injection of the toxic compound into the selected region of the CNS.

“In the toxic animal models such as lysolecithin and ethidium bromide models, a focal myelin loss is induced by stereotactic injection of the toxic compound into the selected region of the CNS (Yajima and Suzuki, 1979; Woodruff and Franklin, 1999).”

• cites Yajima and Suzuki, 1979; Woodruff and Franklin, 1999Not matched

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

Loss of CXCR4 signaling via either pharmacological blockade or in vivo RNA-silencing led to reduced OPC maturation and remyelination failure in the cuprizone model.

“Loss of CXCR4-signaling via either pharmacological blockade or in vivo RNA-silencing led to reduced OPC maturation and remyelination failure in the cuprizone model (Patel et al., 2010).”

• cites Patel et al., 2010 sourceNot checked — no full text of the source

Complete demyelination in the cortex or the hippocampus is reached after 6 weeks of cuprizone feeding.

“However, complete demyelination in the cortex or the hippocampus is reached after 6 weeks of cuprizone feeding”

CXCR4 was located on NG-2-positive OPC.

“CXCR4 was located on NG-2-positive OPC.”

• cites Patel et al., 2010 sourceNot checked — no full text of the source

Demyelination in the cuprizone model is region-dependent.

“Demyelination in the cuprizone model is region-dependent.”

Frequently the cuprizone model is used in parallel to EAE or other animal models to study treatment effects of substances that promote remyelination, such as benztropine, quentiapine fumarate, or antagonists of LINGO-1.

“Frequently the model is used in parallel to EAE or other animal models to study treatment effects of substances that promote remyelination, such as benztropine, quentiapine fumarate, or antagonists of LINGO-1 (Mi et al., 2009; Deshmukh et al., 2013; Zhornitsky et al., 2013).”

• cites Mi et al., 2009; Deshmukh et al., 2013; Zhornitsky et al., 2013Not matched

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

Different protocols for the duration of cuprizone treatment, concentration of cuprizone used, and time points of investigations lead to difficulties in the interpretation of the data.

“There are different protocols for the duration of cuprizone treatment, concentration of cuprizone used, and time points of investigations which leads to difficulties in the interpretation of the data.”