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

In the paper

“Thus, it seems that initially oligodendrocytes are dying due to caspase-3-dependent apoptosis, while later caspase-3-independent apoptosis predominates.”

What the sources say

• Partly supported

  The Results report activated caspase 3 in 97 ± 5% of apoptotic cells on day 6, falling to none of the dying cells on day 21. The Discussion interprets this as a possible switch to caspase-3-independent cell death in the cuprizone model, but treats the involvement of apoptotic-like mechanisms at later stages as speculation rather than establishing that caspase-3-independent apoptosis predominates. (LLM, conf=0.84)

  cites Hesse et al., 2010 sourceExperimental — accuracy not yet measured
• Disputed

  The Results section (‘Cuprizone induces caspase-independent AIF-mediated cell death’; page unavailable) reports no caspase-3 activation after three weeks of cuprizone treatment. The Discussion also describes caspase-independent oligodendrocyte apoptosis in the earliest lesions examined. The paper therefore does not support—and its findings run contrary to—the proposed shift from initially caspase-3-dependent to later caspase-3-independent death. (LLM, conf=0.88)

  Checked by a reasoning model — may be wrong.

  cites Veto et al., 2010 sourceExperimental — accuracy not yet measured

In the paper

“Cortical demyelination can be observed after 3 weeks of cuprizone exposure being almost complete after 6 weeks of cuprizone treatment (Skripuletz et al., 2008; Gudi et al., 2009).”

What the sources say

• Partly supported

  The ‘Cortical De-and Remyelination’ results report significant cortical myelin loss after 4 weeks in C57BL/6 mice and no detectable cortical myelin after 6 weeks. They do not support the claimed 3-week onset; the strain-dependency results also report no cortical myelin loss in BALB/cJ mice before 6 weeks. (LLM, conf=0.88)

  cites Skripuletz et al., 2008 sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites Gudi et al., 2009 source

In the paper

“In contrast, the course of de- and remyelination was similar between genders in C57BL/6 mice (Taylor et al., 2010).”

What the sources say

• Supported

  The Results section reports that cuprizone-exposed male and female C57BL/6 mice had similar demyelination at the measured time points and that remyelination progressed similarly. The finding is limited to the time points tested. (LLM, conf=0.94)

  cites Taylor et al., 2010 source

In the paper

“Demyelination peaks between 4.5 and 5 weeks of cuprizone exposure in the CC and between 5 and 6 weeks in the cortex and hippocampus (Hiremath et al., 1998; Matsushima and Morell, 2001; Skripuletz et al., 2008; Gudi et al., 2009; Koutsoudaki et al., 2009).”

What the sources say

• ?Not checked — no full text of the sourcecites Hiremath et al., 1998 source
• ?Could not verify

  The available paper text describes cuprizone-induced demyelination in mouse brain but gives no peak times for the corpus callosum, cortex, or hippocampus. Searches for the named regions and the 4.5–6-week intervals found no passage addressing those specific timings; the returned passages have no section or page labels. (LLM, conf=0.72)

  cites Matsushima and Morell, 2001 sourceExperimental — accuracy not yet measured
• Partly supported

  The section “Cortical De-and Remyelination Is Prominent in the Cuprizone Model” reports complete cortical myelin loss after six weeks. The section comparing cortex with corpus callosum says their time courses were nearly identical; it does not establish an earlier corpus-callosum peak at 4.5–5 weeks. The cited passages do not address hippocampal demyelination. (LLM, conf=0.87)

  cites Skripuletz et al., 2008 sourceExperimental — accuracy not yet measured

In the paper

“Microglia are brain-resident mononuclear phagocytes that originate from primitive macrophages in the embryonic yolk sac and colonize the neuroepithelium (in mice from day E9.5) at the onset of vascularization of the CNS (Harry and Kraft, 2012; Ginhoux et al., 2013).”

What the sources say

• Partly supported

  Section 3 says immature yolk-sac macrophages are the predominant source of microglia and that initial brain colonization corresponds to the onset of CNS vascularization. It also reports myeloid cells in the mouse brain from gestational day 9.5. The claim states yolk-sac origin without the paper’s qualification that the precise origin remains debated. (LLM, conf=0.82)

  cites Harry and Kraft, 2012 sourceExperimental — accuracy not yet measured
• Partly supported

  The figure caption in “The yolk sac hypothesis of microglial origin” says primitive macrophages leave the yolk sac and colonize the neuroepithelium from E9.5 to give rise to microglia. The paper links their spread to the onset of circulation, but the passages do not establish that colonization occurs at the onset of CNS vascularization. (LLM, conf=0.84)

  cites Ginhoux et al., 2013 sourceExperimental — accuracy not yet measured

In the paper

“Remyelination is very robust in the cuprizone model and starts directly after demyelination is complete, irrespective if cuprizone is further fed or not (Matsushima and Morell, 2001; Hiremath et al., 2008; Gudi et al., 2009).”

What the sources say

• Partly supported

  The paper’s summary reports almost complete remyelination within weeks after cuprizone is stopped. It also reports progenitor-cell proliferation during continued exposure, but that is not evidence that remyelination starts immediately after demyelination is complete or proceeds irrespective of continued feeding. The retrieved passages have no section or page labels. (LLM, conf=0.85)

  cites Matsushima and Morell, 2001 sourceExperimental — accuracy not yet measured
• Partly supported

  The Materials and Methods section says total demyelination is usually observed after six weeks of cuprizone treatment, and the Discussion refers to remyelination at weeks 7 and 8. The paper does not establish that remyelination starts directly after demyelination, is very robust, or occurs irrespective of whether cuprizone feeding continues. Page numbers are unavailable in our copy. (LLM, conf=0.82)

  cites Hiremath et al., 2008 sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites Gudi et al., 2009 source

In the paper

“Probably primarily due to the higher amount of myelin content/debris, a significantly stronger microgliosis can be observed in the cerebellar white matter as compared to the gray matter structures (Skripuletz et al., 2008; Gudi et al., 2009).”

What the sources say

• Partly supported

  The section “Cortical Microglia Response in De-and Remyelination Is Strain-Dependent” (page unavailable) reports more microglia in the corpus callosum than in the cortex of cuprizone-treated C57BL/6 mice. It does not examine cerebellar white and gray matter or establish that greater myelin content or debris causes the difference. The reported response is also strain-dependent. (LLM, conf=0.84)

  cites Skripuletz et al., 2008 sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites Gudi et al., 2009 source

In the paper

“Recently, the expression of the radial glia cell marker fatty acid binding protein 7 (FABP7) was found to be induced in activated astrocytes after cuprizone-induced acute demyelination whereas expression of this marker and the extent of astrogliosis was diminished after chronic demyelination (Kipp et al., 2011a).”

What the sources say

• Partly supported

  The sections on cuprizone-induced demyelination and FABP7 expression report abundant FABP7 in the acutely demyelinated corpus callosum and identify FABP7-positive, GFAP-positive astrocyte-like cells after acute treatment (page unavailable). The paper compares remyelination after acute and chronic treatment, but our copy does not report diminished FABP7 expression or diminished astrogliosis after chronic demyelination. (LLM, conf=0.85)

  cites Kipp et al., 2011a sourceExperimental — accuracy not yet measured

In the paper

“Since Gas6-deficient mice, challenged with cuprizone, display a potentiated demyelination and microglia activation”

What the sources say

• Supported

  In “Demyelination is increased in Gas6−/− mice,” cuprizone-challenged Gas6-deficient mice had significantly greater demyelination than challenged wild-type mice. “Microglial activity is increased in Gas6 KO mice challenged with cuprizone” reports significantly more IBA1-positive cells in the deficient mice. Both genotype differences were observed in the rostral corpus callosum; the indexed passages provide no specific page number. (LLM, conf=0.92)

  cites Binder et al., 2008 source

In the paper

“After cessation of cuprizone treatment after acute and chronic demyelination astrogliosis is persisting over a period of weeks during the remyelination period, which is in contrast to the transient activation of microglia (Skripuletz et al., 2011a; Hibbits et al., 2012).”

What the sources say

• ?Not matched

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

  cites Skripuletz et al., 2011a
• Supported

  The Introduction states that astrocyte reactivity continues through a 6-week recovery period after cuprizone treatment, in contrast with microglial activation. The Results (Figure 2) show persistent astrocyte reactivity during recovery after both acute and chronic demyelination, while microglial activation attenuates. (LLM, conf=0.94)

  cites Hibbits et al., 2012 source

In the paper

“Upon cuprizone treatment Tyro3 gene expression was down-regulated and seems to coincide with oligodendroglial loss, while Axl and Mer were found on activated microglia (Binder et al., 2008).”

What the sources say

• Supported

  In “Gas6 and its receptors are regulated in a mouse model of demyelination” (page unavailable), the paper reports reduced Tyro3 gene expression during cuprizone-induced demyelination. The Discussion (page unavailable) says this expression is negatively correlated with oligodendrocyte damage or death. The paper also finds Axl and Mer expression on microglia during cuprizone challenge. (LLM, conf=0.93)

  cites Binder et al., 2008 source

In the paper

“IL-1β is another prominent pro-inflammatory cytokine that is produced primarily by activated microglia and macrophages (Giulian et al., 1986; Sairanen et al., 1997).”

What the sources say

• Partly supported

  The Results (p. 597) show that stimulated rat microglia release IL-1, and the Discussion (p. 602) identifies ameboid microglia as the major producers of brain IL-1 in vitro. The paper also discusses macrophage IL-1, but it does not identify the measured cytokine specifically as IL-1β or establish that microglia and macrophages are its primary producers generally. (LLM, conf=0.88)

  cites Giulian et al., 1986 sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites Sairanen et al., 1997 source

In the paper

“Interestingly, depletion of TNF-α did not alter the extent of microglial or astroglial responses, however, it displayed significant effects on expression of inflammatory genes.”

What the sources say

• Partly supported

  The ‘Expression of MHC-I and -II during demyelination and remyelination’ section (page unavailable) reports similar microglia–macrophage recruitment in wild-type and TNF-α-null mice, but significantly lower MHC-I and MHC-II expression without TNF-α. The passages identify astrocytes as sites of MHC expression but do not establish that the extent of the astroglial response was unchanged. (LLM, conf=0.86)

  cites Arnett et al., 2003 sourceExperimental — accuracy not yet measured

In the paper

“Furthermore, MMP are shown to be implicated in numerous regenerative processes (Larsen and Yong, 2004; Yong, 2005; Lehmann et al., 2009).”

What the sources say

• Supported

  The Introduction links MMP activity to remyelination after injury and neurite extension, and describes these as beneficial functions relevant to recovery. This supports the broad statement that MMPs are implicated in multiple regenerative processes. (LLM, conf=0.88)

  cites Larsen and Yong, 2004 source
• ?Not checked — no full text of the sourcecites Yong, 2005 source
• ?Not checked — no full text of the sourcecites Lehmann et al., 2009 source

In the paper

“Matrix metalloproteinases (MMP), a family of zinc-dependent endopeptidases, are highly involved in the perpetuation of inflammation, myelin degradation, and remodeling of extracellular matrix”

What the sources say

• ?Not checked — no full text of the sourcecites McCawley and Matrisian, 2001 source
• Partly supported

  Section 4.6 (page not provided) says MMPs contribute to tissue inflammation and extracellular-matrix destruction and remodeling in CNS disease. Section 4.3 also links them to inflammatory responses in arthritis. Neither section states that MMPs degrade myelin, so that part of the claim is unsupported by our copy. (LLM, conf=0.87)

  cites Malemud, 2006 sourceExperimental — accuracy not yet measured

In the paper

“Interestingly, accumulation of microglia and proliferation of OPC were not altered in the IL-1β −/− mice.”

What the sources say

• Partly supported

  The results sections report similar microglia-macrophage numbers and similar accumulation of NG2-positive oligodendrocyte progenitors in IL-1β-deficient and wild-type mice after five weeks of cuprizone exposure. The Discussion says progenitor accumulation could result from migration and/or local proliferation; it does not establish that OPC proliferation itself was unaltered. (LLM, conf=0.87)

  cites Mason et al., 2001 sourceExperimental — accuracy not yet measured

In the paper

“Later, the same group reported an enhanced remyelination, increased regeneration, and reduced apoptosis of oligodendrocytes in the hPDGFα-GFAP mice (exploited also by Woodruff et al., 2004) after chronic cuprizone intoxication (Vana et al., 2007).”

What the sources say

• Supported

  The Results sections report greater remyelination and oligodendrocyte repopulation in hPDGF-A transgenic mice than in wild-type mice during recovery from chronic cuprizone demyelination. They also report fewer apoptotic cells during that recovery period, including cells of the oligodendrocyte lineage. The reduction in apoptosis is specific to recovery, not the entire cuprizone-treatment period. (LLM, conf=0.88)

  cites Vana et al., 2007 source

In the paper

“suggesting that FGF-2 may not be an essential/exclusive mitogenic factor for OPC in vivo, and may even predominantly promote an inhibitory effect impeding OPC differentiation and remyelination (Armstrong et al., 2006).”

What the sources say

• Supported

  The Discussion reports similar progenitor and cycling-cell densities in FGF2 wild-type and null mice and concludes that endogenous FGF2 is not a predominant mitogen in the acute cuprizone model. The Introduction identifies inhibition of progenitor differentiation as FGF2’s predominant in vivo effect during remyelination, while the Discussion reports improved remyelination when FGF2 is absent. (LLM, conf=0.91)

  cites Armstrong et al., 2006 source

In the paper

“Nevertheless, Mana et al. reported an increased number of NG2-positive cells in IFN-γR −/− mice in comparison to wild type (wt) mice suggesting inhibitory/harmful effects of IFN-γ on OPC recruitment/survival and remyelination (Mana et al., 2006).”

What the sources say

• Supported

  The OPC results section reports significantly more NG2-positive cells in IFN-γR−/− mice than in wild-type mice after three weeks of cuprizone feeding. The Discussion interprets the findings as suggesting that IFN-γ inhibits OPC recruitment and interferes with remyelination. The claim’s suggested harmful effect is consistent with that interpretation. (LLM, conf=0.94)

  cites Mana et al., 2006 source

In the paper

“On the other hand, the absence of constitutively expressed neuronal NO synthase (nNOS) protected the mice from cuprizone-induced demyelination, reduced the inflammatory glial response and oligodendroglial apoptosis, but also impaired OPC accumulation and subsequent remyelination (Linares et al., 2006).”

What the sources say

• Supported

  The Results report less cuprizone-induced demyelination, inflammatory-cell accumulation, astrocytosis, and apoptosis in nNOS-deficient mice. Figure 7 reports fewer accumulating OPCs, while the demyelination/remyelination Results report slower remyelination after cuprizone removal. The paper describes the remyelination impairment as transient: both groups showed myelin staining throughout the corpus callosum four weeks after removal. (LLM, conf=0.91)

  cites Linares et al., 2006 source

In the paper

“In the CC of cuprizone-treated mice the expression of the IGF-1 mRNA started to be up-regulated after 2 weeks of cuprizone feeding (Gudi et al., 2011) and peaked at weeks 4–5 corresponding to the maximal demyelination, proliferation of OPC and onset of their differentiation (Gudi et al., 2011).”

What the sources say

• Partly supported

  The Results section on growth-factor mRNA expression reports that IGF-1 mRNA peaked at week 4.5, coinciding with peak demyelination; the Discussion also links that time point to intensive OPC proliferation. The copy describes a gradual rise but does not establish that IGF-1 up-regulation began specifically after two weeks. The Results show mature oligodendrocytes reappearing at week 5, but do not directly identify the onset of OPC differentiation at weeks 4–5. Page numbers are unavailable in the indexed copy. (LLM, conf=0.84)

  cites Gudi et al., 2011 sourceExperimental — accuracy not yet measured

In the paper

“Komoly et al. investigated de- and remyelination in the cerebellar peduncles in swiss Webster mice exposed to 0.6% (w/w) cuprizone and found an astrocytic expression of IGF-1, whereas IGF-1 receptor (IGF1R) was transiently expressed in OPC (Komoly et al., 1992) during the early recovery phase.”

What the sources say

• Partly supported

  The Abstract reports astrocytic IGF-I expression in areas of myelin breakdown and a transient increase in IGF-I receptor expression in immature oligodendroglia during early recovery. It says astrocytic expression decreased rapidly during recovery, rather than placing its induction in that phase. The available text also does not specify the cited Swiss Webster strain or 0.6% cuprizone concentration. (LLM, conf=0.84)

  cites Komoly et al., 1992 sourceExperimental — accuracy not yet measured

In the paper

“In Zhou et al. study after a recovery period for additional 6 weeks, OPC numbers were diminished and the number of mature oligodendrocytes was increased, indicating a beneficial effect of FGFR1 reduction on OPC differentiation (Zhou et al., 2012).”

What the sources say

• Supported

  The Abstract states that after a six-week recovery period, oligodendrocyte progenitor numbers fell and mature oligodendrocyte numbers rose, indicating an effect of FGFR1 reduction on differentiation. The Results section on FGFR1 regulation of recovery following chronic demyelination reports fewer progenitors in treated mice and greater oligodendrocyte recovery after six weeks; the paper also reports enhanced remyelination. The citing sentence's description of the effect as beneficial is consistent with those findings. (LLM, conf=0.94)

  cites Zhou et al., 2012 source

In the paper

“Additionally, these mice exhibited an enhanced demyelination at week 3 but an almost complete myelin recovery at week 5 in contrast to wt mice undergoing a severe myelin deficit at this time point.”

What the sources say

• Partly supported

  The ‘Early recovery from acute demyelination in IGF-1 tg mice’ section reports significant demyelination in both groups at week 3, followed by substantial remyelination in IGF-1 transgenic mice and nearly complete demyelination in wild-type mice at week 5. It does not support greater week-3 demyelination in the transgenic mice; it suggests their demyelinating insult was less extensive. (LLM, conf=0.86)

  cites Mason et al., 2000b sourceExperimental — accuracy not yet measured

In the paper

“In our own studies we found that the FGF-2 mRNA expression began to increase already from the first weeks of cuprizone feeding and was even stronger up-regulated after 4 weeks (severe demyelination) corresponding to the intensive proliferation of OPC (Gudi et al., 2011).”

What the sources say

• Supported

  The Results section reports elevated FGF-2 mRNA during demyelination, with a peak in the corpus callosum at weeks 4–4.5. The Discussion links strong up-regulation at 4.5 weeks to intensive OPC proliferation. The cited sentence rounds that time point to four weeks. (LLM, conf=0.88)

  cites Gudi et al., 2011 source

In the paper

“Later, Mana et al. reported a deleterious role of IFN-γ demonstrating reduced demyelination and enhanced remyelination in mice lacking the binding chain of the IFN-γ receptor (Mana et al., 2006).”

What the sources say

• Supported

  The Discussion reports delayed demyelination in cuprizone-fed mice lacking the binding chain of the IFN-γ receptor and faster remyelination after cuprizone removal. The paper characterizes these findings as suggesting a deleterious role for IFN-γ in this model. (LLM, conf=0.94)

  cites Mana et al., 2006 source

In the paper

“The chemokine CXCL12 is a potent chemoattractant for lymphocytes and monocytes but not neutrophils (Bleul et al., 1996).”

What the sources say

• Supported

  The Introduction (p. 1101) describes SDF-1 as a highly efficacious lymphocyte chemoattractant and states that it is active on monocytes but not neutrophils in vitro. This supports the cited claim; the neutrophil finding is specifically an in vitro result. (LLM, conf=0.94)

  cites Bleul et al., 1996 source

In the paper

“The deficiency of this chemokine resulted in the reduced recruitment of microglia and astrocytes as reflected by delayed demyelination and an attenuated TNF-α secretion after 3.5 weeks of cuprizone ingestion (McMahon et al., 2001).”

What the sources say

• Partly supported

  The Results report fewer microglia/macrophages and astrocytes and less demyelination in MIP-1α-deficient mice after 3.5 weeks of cuprizone treatment. They also report lower TNF-α levels across treatment time points, most evidently at 4 weeks. The Discussion cautions that reduced cell counts do not establish reduced recruitment—particularly for astrocytes, whose recruitment by MIP-1α the authors say is unclear. (LLM, conf=0.85)

  cites McMahon et al., 2001 sourceExperimental — accuracy not yet measured

In the paper

“However, this augmented pool of OPC failed to differentiate into mature oligodendrocytes and to enhance remyelination, probably due to induction of apoptosis in these cells by exogenously administered BMP4.”

What the sources say

• Supported

  The Results report that BMP4 infusion increased OPC numbers during cuprizone-induced demyelination, but the Discussion says oligodendroglial numbers fell after recovery. The remyelination Results found less myelin staining in BMP4-infused mice than in controls. The Discussion suggests that BMP4-promoted apoptosis could explain the loss of OPCs; the claim’s “probably” preserves that uncertainty. (LLM, conf=0.87)

  cites Sabo et al., 2011 source

In the paper

“TGF-β1 mRNA expression itself was significantly enhanced during cuprizone ingestion showing the same temporal pattern as IGF-1 (Gudi et al., 2011).”

What the sources say

• Supported

  The Results section, “Analysis of growth factor mRNA expression profiles,” reports that TGF-β1 and IGF-1 mRNA increased significantly after cuprizone treatment, peaked together at 4.5 weeks, and then declined. The Results section on temporal patterns also assigns both factors the same expression pattern. (LLM, conf=0.94)

  cites Gudi et al., 2011 source

In the paper

“Interestingly, mice lacking TNFR2 displayed a loss of CXCL12 up-regulation in astrocytes and concomitant reduction in the number of NG2- CXCR4-positive OPC leading to delayed remyelination in the cuprizone model (Patel et al., 2012).”

What the sources say

• Supported

  The Introduction reports that TNFR2-deficient mice lack astrocyte CXCL12 up-regulation and have fewer CXCR4-positive OPCs during cuprizone-induced demyelination. The Abstract identifies these OPCs as CXCR4-positive and NG2-positive; the Discussion states that TNFR2-deficient mice exhibit delayed remyelination after cuprizone cessation. (LLM, conf=0.91)

  cites Patel et al., 2012 source

In the paper

“However, the clearance of damaged myelin as well as the recruitment of microglia was strongly impaired in this experimental setting”

What the sources say

• ?Not checked — no full text of the sourcecites Skripuletz et al., 2013 source

In the paper

“These observations pointed to a more complex mode of action that is not only based on the copper-chelating properties but may also regulate other cellular processes.”

In the paper

“In this case the remyelination capacity retains after withdrawal from cuprizone diet but is strongly decreased (Ludwin, 1980; Lindner et al., 2009).”

What the sources say

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

In the paper

“It needs to be emphasized that all these models, including EAE, mimic only a part of MS pathology.”

In the paper

“Remarkably, the susceptibility to cuprizone, extent of hydrocephalus, spatiotemporal pattern of de- and remyelination or the glial reaction are varying between species, mice strains or simply between different brain regions (Carlton, 1969; Kimberlin et al., 1976; Love, 1988; Stidworthy et al., 2003; Adamo et al., 2006; Skripuletz et al., 2010a), suggesting that the local cellular microenvironment”

What the sources say

• ?Not checked — no full text of the sourcecites Carlton, 1969 source
• ?Not checked — no full text of the sourcecites Kimberlin et al., 1976 source
• ?Not checked — no full text of the sourcecites Love, 1988 source

In the paper

“The pathology of MS lesions is heterogeneous (Lucchinetti et al., 2000) and several patterns suggesting predominant immune-mediated inflammation (pattern I and II) and primary oligodendrogliopathy (pattern III and IV) have been described (Lucchinetti et al., 1996, 2000).”

What the sources say

• ?Not checked — no full text of the sourcecites Lucchinetti et al., 2000 source

In the paper

“The so called cuprizone model is a toxic model of demyelination in the CNS white and gray matter, which lacks an autoimmune component.”

In the paper

“Pasquini et al. reported a marked decrease in the activities of complex I, II, and III of the respiratory chain in oligodendrocyte cultures treated with cuprizone and in mitochondria isolated from cuprizone-treated mice confirming that cuprizone disturbs mitochondrial function and thus compromises the energy metabolism of cells (Pasquini et al., 2007).”

What the sources say

• ?Not checked — no full text of the sourcecites Pasquini et al., 2007 source

In the paper

“When mice were fed 0.2% (w/w) cuprizone and copper supplementation was increased to 130ppm the incidence of hydrocephalus declined without any effects on brain oedema and spongy degradation (Carlton, 1967).”

What the sources say

• ?Not checked — no full text of the sourcecites Carlton, 1967 source

In the paper

“Inflammatory metabolites of activated microglia/astrocytes may harm oligodendrocytes as well.”

In the paper

“However, mitochondria seem to be mainly affected by this toxin, leading to increased production of oxidative agents, and disturbance of energy metabolism of oligodendrocytes with subsequent cell death.”

In the paper

“Although remyelination frequently occurs after demyelinating events, it is often incomplete (Patrikios et al., 2006; Goldschmidt et al., 2009).”

What the sources say

• ?Not checked — no full text of the sourcecites Patrikios et al., 2006 source
• ?Not checked — no full text of the sourcecites Goldschmidt et al., 2009 source

In the paper

“The pathology of MS lesions is heterogeneous (Lucchinetti et al., 2000) and several patterns suggesting predominant immune-mediated inflammation (pattern I and II) and primary oligodendrogliopathy (pattern III and IV) have been described (Lucchinetti et al., 1996, 2000).”

What the sources say

• ?Not matched

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

  cites Lucchinetti et al., 1996, 2000

In the paper

“Upon cuprizone-induced demyelination NG-2-positive precursor cells proliferate and accumulate in the subventricular zone (SVZ) at week 2 and then migrate towards demyelinating lesions (Mason et al., 2000a).”

What the sources say

• ?Not checked — no full text of the sourcecites Mason et al., 2000a source

In the paper

“In the cerebellum microgliosis occurred delayed (from week 6 to 10), but followed a white–gray matter gradient as well (Skripuletz et al., 2010a).”

What the sources say

• ?Not checked — no full text of the sourcecites Skripuletz et al., 2010a source

In the paper

“Successful remyelination comprises several highly orchestrated events including migration, proliferation, terminal differentiation of OPC, and myelination (Stangel and Hartung, 2002).”

What the sources say

• ?Not checked — no full text of the sourcecites Stangel and Hartung, 2002 source

In the paper

“Under continuing cuprizone treatment astrogliosis persists and after chronic demyelination the number of astrocytes is similar to acute demyelination (Lindner et al., 2009; Kipp et al., 2011b).”

What the sources say

• ?Not checked — no full text of the sourcecites Lindner et al., 2009 source
• ?Not checked — no full text of the sourcecites Kipp et al., 2011b source

In the paper

“Ablation of astrocytes during cuprizone-induced demyelination had no impact on the loss of mature oligodendrocytes and on axonal damage, but resulted in a diminished activation and invasion of microglia into the demyelinated lesion.”

What the sources say

• ?Not checked — no full text of the sourcecites Skripuletz et al., 2013 source

In the paper

“Altogether, the results suggest that in cuprizone-induced de- and remyelination activated microglia play a crucial role creating a repair promoting environment due to myelin debris clearance proceeding in a highly controlled manner, as well as by production of cytokines/growth factors essential for oligodendrocyte lineage cells.”

In the paper

“In response to different CNS pathologies astrocytes become activated whereupon GFAP-expression is increased and hypertrophy of cellular processes occurs, a process called astrogliosis (Pekny and Nilsson, 2005).”

What the sources say

• ?Not checked — no full text of the sourcecites Pekny and Nilsson, 2005 source

In the paper

“In respect to the M1/M2 classification it seems that the microglia population in the cuprizone model is either heterogeneously composed of both M1 and M2 phenotypes or microglia display an intermediate status.”

In the paper

“Gas6 is acting on three tyrosine kinase receptors Tyro3, Axl, and Mer (Lai and Lemke, 1991).”

What the sources say

• ?Not checked — no full text of the sourcecites Lai and Lemke, 1991 source

In the paper

“As a consequence the removal of myelin debris was delayed and subsequent OPC proliferation and remyelination were delayed.”

What the sources say

• ?Not checked — no full text of the sourcecites Skripuletz et al., 2013 source

In the paper

“Mice lacking Lt-α showed a decreased number of microglia and delayed demyelination as well as reduced loss of mature oligodendrocytes at week 3.5 (Plant et al., 2005).”

What the sources say

• ?Not checked — no full text of the sourcecites Plant et al., 2005 source

In the paper

“TNF-α is a multipotent inflammatory cytokine, which can act through two receptors, TNFR1(p55) and TNFR2(p75) (Vandenabeele et al., 1995; Locksley et al., 2001), triggering multiple and sometimes opposing effects (apoptosis vs. proliferation).”

What the sources say

• ?Not checked — no full text of the sourcecites Vandenabeele et al., 1995 source
• ?Not checked — no full text of the sourcecites Locksley et al., 2001 source

In the paper

“In the cuprizone model, TNF-α was demonstrated to act as well in a bivalent manner since TNF-α −/− mice displayed a reduced loss of oligodendrocytes during the first 3.5 weeks of cuprizone feeding but also a significantly diminished ability to remyelinate (Arnett et al., 2001).”

What the sources say

• ?Not checked — no full text of the sourcecites Arnett et al., 2001 source

In the paper

“whereas MMP12 appeared in microglia, astrocytes and during the remyelination phase in oligodendrocytes as well.”

What the sources say

• ?Not checked — no full text of the sourcecites Skuljec et al., 2011 source

In the paper

“It is widely accepted that the main impact of FGF-2 on OPC is the induction/support of proliferation (Bansal et al., 1996), inhibition of progenitor differentiation, and subsequent myelination (Bansal and Pfeiffer, 1997; Goddard et al., 2001; Murtie et al., 2005a,b; Zhou et al., 2006).”

What the sources say

• ?Not checked — no full text of the sourcecites Bansal et al., 1996 source
• ?Not checked — no full text of the sourcecites Bansal and Pfeiffer, 1997 source
• ?Not checked — no full text of the sourcecites Goddard et al., 2001 source

In the paper

“Nevertheless, the remyelination capacity was significantly improved in mice lacking IFN-γ, probably linked to reduced endoplasmic reticulum stress via IFN-γ (Lin et al., 2006).”

What the sources say

• ?Not checked — no full text of the sourcecites Lin et al., 2006 source

In the paper

“Additionally, OPN was reported to enhance the proliferation capacity of OPC cell lines and promote both MBP synthesis and myelin formation in mixed cortical cultures, suggesting to be involved in remyelination (Selvaraju et al., 2004).”

What the sources say

• ?Not checked — no full text of the sourcecites Selvaraju et al., 2004 source

In the paper

“we believe that FGF-2 modulates not solely the oligodendrocyte lineage but may also influence the action/interaction of astrocytes and microglia.”

In the paper

“Thus, it can be suggested that FGF-2 possesses multiple functions and acts not only directly on oligodendrocytes but also influences other cell types promoting myelination indirectly.”

In the paper

“First Gao et al. proposed protective effects of IFN-γ on myelin using mice that ectopically expressed a low level of IFN-γ under the MBP promoter in oligodendrocytes (Gao et al., 2000).”

What the sources say

• ?Not checked — no full text of the sourcecites Gao et al., 2000 source

In the paper

“IGF-1 is believed to play a crucial role in oligodendrocyte differentiation, survival, and myelination (Mozell and Mcmorris, 1991; Barres et al., 1992, 1993; Goddard et al., 1999; Ye and D'Ercole, 1999).”

What the sources say

• ?Not checked — no full text of the sourcecites Mozell and Mcmorris, 1991 source
• ?Not checked — no full text of the sourcecites Barres et al., 1992 source
• ?Not checked — no full text of the sourcecites Goddard et al., 1999 source

In the paper

“IGF-1 over-expressing mice showed hypermyelinated axons (Ye et al., 1995), whereas IGF-1 knockout mice exhibited a decreased number of oligodendrocytes and hypomyelination (Beck et al., 1995; Ye et al., 2002).”

What the sources say

• ?Not matched

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

  cites Ye et al., 1995
• ?Not checked — no full text of the sourcecites Beck et al., 1995 source
• ?Not matched

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

  cites Ye et al., 2002

In the paper

“EAE studies using neutralizing antibodies against CCL2 and CCL3 suggested that CCL3 controls accumulation of mononuclear cell during acute EAE, correlating with increasing acute disease severity, while CCL2 was responsible for a mononuclear cell infiltration during relapsing EAE (Karpus et al., 1995; Kennedy et al., 1998).”

What the sources say

• ?Not matched

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

  cites Karpus et al., 1995; Kennedy et al., 1998

In the paper

“OPC and mature oligodendrocytes express BMP4 and its receptors (Kondo and Raff, 2004).”

What the sources say

• ?Not checked — no full text of the sourcecites Kondo and Raff, 2004 source

In the paper

“arguing for a direct effect of LIF on differentiated oligodendrocyte survival and myelination (Marriott et al., 2008).”

What the sources say

• ?Not checked — no full text of the sourcecites Marriott et al., 2008 source

In the paper

“However, it becomes more and more evident that different chemokines are also implicated in a variety of fundamental biological functions including proliferation, migration, and differentiation of different cell types playing a crucial role in development, homeostasis, and plasticity of the immune system and the CNS (Zou et al., 1998; Bajetto et al., 2002; Rezaie et al., 2002; Tran and Miller, 2003”

What the sources say

• ?Not matched

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

  cites Zou et al., 1998; Bajetto et al., 2002; Rezaie et al., 2002; Tran and Miller, 2003; Le et al., 2004; Tran et al., 2004; Raman et al., 2011

In the paper

“CCL2 has been shown to be produced by astrocytes in EAE (Ransohoff et al., 1993; Adamus et al., 1997).”

What the sources say

• ?Not matched

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

  cites Ransohoff et al., 1993; Adamus et al., 1997

In the paper

“Both molecules possess multiple functions in a variety of cell types including promotion of oligodendrogenesis, differentiation, myelin synthesis, and survival of oligodendrocytes (Mayer et al., 1994; Barres et al., 1996; Marmur et al., 1998; Stankoff et al., 2002; Talbott et al., 2007; Ishibashi et al., 2009) in vitro and in vivo”

What the sources say

• ?Not matched

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

  cites Mayer et al., 1994; Barres et al., 1996; Marmur et al., 1998; Stankoff et al., 2002; Talbott et al., 2007; Ishibashi et al., 2009

In the paper

“Production of CCL3 in murine cortical astrocytes was also regulated after an inflammatory stimulus such as LPS (Murphy et al., 1995).”

What the sources say

• ?Not checked — no full text of the sourcecites Murphy et al., 1995 source

In the paper

“Interestingly, LIF can inhibit the production of the pro-inflammatory cytokine TNF-α and reactive oxygen species (ROS) by macrophages probably limiting a progression of inflammation and acting anti-apoptotic (Hendriks et al., 2008).”

What the sources say

• ?Not checked — no full text of the sourcecites Hendriks et al., 2008 source

In the paper

“In vitro treatment of OPC with BMP4 inhibited their differentiation but promoted differentiation of astrocytes (Mabie et al., 1997; Grinspan et al., 2000).”

What the sources say

• ?Not matched

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

  cites Mabie et al., 1997; Grinspan et al., 2000

In the paper

“Exogenously administered LIF limited cuprizone-induced demyelination in wt mice and rescued the LIF-knockout phenotype during cuprizone-induced demyelination.”

What the sources say

• ?Not checked — no full text of the sourcecites Marriott et al., 2008 source

In the paper

“CCL3 has been reported to be produced by lipopolysaccharide (LPS)-stimulated microglia and is implicated in the migration and activation of these glial cells in vitro and in vivo (Hayashi et al., 1995; Cross and Woodroofe, 1999; Selenica et al., 2013).”

What the sources say

• ?Not matched

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

  cites Hayashi et al., 1995; Cross and Woodroofe, 1999; Selenica et al., 2013

In the paper

“In cuprizone-induced demyelination LIF-deficient mice displayed more severe demyelination, increased loss of oligodendrocytes, and an impaired remyelination (Emery et al., 2006; Marriott et al., 2008).”

What the sources say

• ?Not matched

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

  cites Emery et al., 2006; Marriott et al., 2008

In the paper

“Since multiple environmental factors such as Epstein-Barr Virus (EBV) infections were suggested to be strongly linked to the development of MS”

What the sources say

• ?Not matched

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

  cites Suckling et al., 1978; Serafini et al., 2007; Drescher and Sosnowska, 2008; Lane and Hosking, 2010; Tsunoda and Fujinami, 2010

In the paper

“One of the major drawbacks of these models is the need of an exact stereotactic surgical procedure. Furthermore, the application of the toxin produces a stab wound that may complicate the molecular processes.”

What the sources say

• ?Not matched

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

  cites Table 1

In the paper

“Cuprizone-induced demyelination is age-, and in some strains also gender-dependent.”

In the paper

“The spatiotemporal pattern of cuprizone-induced de- and remyelination is brain region specific and may even vary within a structure like the CC.”

In the paper

“When cuprizone is fed even longer these oligodendrocytes are damaged again and the myelin disappears after week 6.”

In the paper

“In the last two decades mice of the C57BL/6 background were mainly used for investigations and are thus the best-characterized strain.”

In the paper

“Despite continued cuprizone exposure mature oligodendrocytes occur between week 5 and 6 and start subtle remyelination.”

In the paper

“Astrocytic expression of CXCL12 was detected in MS lesions and could be as well induced upon IL-1β, TNF-α, and MBP stimulation in vitro (Ambrosini et al., 2005; Calderon et al., 2006).”

What the sources say

• ?Not matched

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

  cites Ambrosini et al., 2005; Calderon et al., 2006

In the paper

“However, the aetiology of MS remains still unresolved and the pathology of MS lesions as well as the individual course of disease are highly heterogeneous (Lucchinetti et al., 2000; Lassmann et al., 2007).”

What the sources say

• ?Not matched

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

  cites Lucchinetti et al., 2000; Lassmann et al., 2007

In the paper

“The dose of cuprizone needs to be adjusted in accordance to species, mouse strains, and age of animals.”

In the paper

“Since lesion induction is not immune-mediated it is quite different to MS.”

In the paper

“Furthermore, the cuprizone model allows to dissect the molecular mechanisms without the interference with the peripheral immune system, which is rather difficult in EAE.”

In the paper

“However, since the pathomechanisms of MS are highly complex none of these models reflects the whole spectrum of MS and due to an artificial way of induction all these models have their limitation (Table 1).”

What the sources say

• ?Not matched

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

  cites Table 1

In the paper

“EAE reflects the autoimmune origin of MS and is probably the most frequently used model that already has been proven as extremely useful to develop/establish/test some of the currently available immunomodulating MS therapeutics (Gold et al., 2000, 2006; Constantinescu et al., 2011).”

What the sources say

• ?Not matched

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

  cites Gold et al., 2000, 2006; Constantinescu et al., 2011

In the paper

“Many investigators feed C57BL/6 mice with 0.2% (w/w) cuprizone for 6 weeks to achieve complete demyelination.”

In the paper

“Most studies in this model were performed in mice, but rats, guinea pigs, and hamsters are also susceptible to cuprizone.”

In the paper

“Cuprizone treatment is a good model to study remyelination and to answer general neurobiological questions of glial reactions after a demyelinating insult (Skripuletz et al., 2011a, 2013; Zendedel et al., 2013).”

What the sources say

• ?Not matched

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

  cites Skripuletz et al., 2011a, 2013; Zendedel et al., 2013

In the paper

“Thus, it should be kept in mind that remyelination does not strictly start with the end of cuprizone administration but all the necessary prerequisites are already made available before that.”

In the paper

“After chronic demyelination (12 weeks) the remyelination capacity retains after withdrawal from the cuprizone diet but is strongly decreased.”

In the paper

“For young male C57BL/6 mice (8–10 weeks old) the cuprizone dose of 0.2% (w/w) is known to be well tolerated and reliable to induce a profound demyelination.”

In the paper

“In contrast, a systemic oral administration of the toxin cuprizone does not require complicated equipment/certain surgical skills and is represented by a relatively simple, but as well highly reproducible and reliable protocol.”

What the sources say

• ?Not matched

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

  cites Table 1

In the paper

“Different myelin proteins are temporally individually degraded and re-expressed.”

In the paper

“Most studies have investigated the medial CC where complete demyelination occurs after 5 weeks of 0.2% (w/w) cuprizone administration.”

In the paper

“The extent of cuprizone-induced demyelination is mouse strain specific.”

In the paper

“CXCL12–CXCR4-signaling plays an important role in the patterning and plasticity of both immune and nervous system during development and adulthood (Klein and Rubin, 2004; Li and Ransohoff, 2008).”

What the sources say

• ?Not matched

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

  cites Klein and Rubin, 2004; Li and Ransohoff, 2008

In the paper

“Genetic models are useful to study dysfunctions of myelination and axonal transport but they are not suitable to investigate remyelination.”

What the sources say

• ?Not matched

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

  cites Table 1

In the paper

“Such substances also affect microglia and astrocytes the reaction of which has not been characterized so far.”

In the paper

“It seems that the regeneration program initiated after the toxic insult via cuprizone proceeds in a highly controlled manner running sequences of tightly orchestrated events on molecular and cellular levels beginning with an activation of microglia and astrocytes as a response to the oligodendrocyte insult within the first 3 weeks of cuprizone feeding followed by a massive proliferation of all gl”

What the sources say

• ?Not matched

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

  cites Figures 3, 4

In the paper

“The cuprizone model is a well established and investigated paradigm to study de- and remyelination in rodents.”

In the paper

“Models using additional inhibitors of proliferation like rapamycin in order to better synchronize remyelination are not well characterized.”

In the paper

“Thus, the system is even more artificial and the interpretation of results may be impossible because beside the oligodendrocyte damage there is interference with all other proliferating cells.”