Cuprizone does not induce <scp>CNS</scp> demyelination in nonhuman primates

Chen, Zhihong; Chen, Jacqueline T.; Johnson, Matthew A.; Gossman, Zachary C.; Hendrickson, Megan; Sakaie, Kenneth Earl; Martinez-Rubio, Clarissa; Gale, John T.; Trapp, Bruce D.

doi:10.1002/acn3.159

Cited by 10 publications

(5 citation statements)

References 17 publications

(17 reference statements)

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“…The following primary antibodies were used: mouse anti-APC (CC1, 1:500, GeneTex Cat# GTX16794, RRID:AB_422,404), rabbit anti-glutathione-S-transferase pi (GSTpi, 1:2000, Enzo Life Sciences, Farmingdale, NY, US Cat# ADI-MSA-101-E, RRID:AB_2,039,147), goat anti-PDGFR (alpha/CD140A, 1:250, Neuromics, Edina, MN, US Cat# GT15150, RRID:AB_2,737,233), and rat anti-PLP [PLP, 1:250, kind gift from B. Trapp and R. Dutta, Dept. of Neurosciences, Cleveland Clinic, OH, USA [36] . Slices were then washed twice in 1x TBS for five minutes each and secondary antibodies were diluted 1:200 and applied for 30 minutes along with DAPI (1:50) in PBS.…”

Section: Methodsmentioning

confidence: 99%

Identification of novel myelin repair drugs by modulation of oligodendroglial differentiation competence

et al. 2021

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Background In multiple sclerosis loss of myelin and oligodendrocytes impairs saltatory signal transduction and leads to neuronal loss and functional deficits. Limited capacity of oligodendroglial precursor cells to differentiate into mature cells is the main reason for inefficient myelin repair in the central nervous system. Drug repurposing constitutes a powerful approach for identification of pharmacological compounds promoting this process. Methods A phenotypic compound screening using the subcellular distribution of a potent inhibitor of oligodendroglial cell differentiation, namely p57kip2, as differentiation competence marker was conducted. Hit compounds were validated in terms of their impact on developmental cell differentiation and myelination using both rat and human primary cell cultures and organotypic cerebellar slice cultures, respectively. Their effect on spontaneous remyelination was then investigated following cuprizone-mediated demyelination of the corpus callosum. Findings A number of novel small molecules able to promote oligodendroglial cell differentiation were identified and a subset was found to foster human oligodendrogenesis as well as myelination ex vivo . Among them the steroid danazol and the anthelminthic parbendazole were found to increase myelin repair. Interpretation We provide evidence that early cellular processes involved in differentiation decisions are applicable for the identification of regeneration promoting drugs and we suggest danazol and parbendazole as potent therapeutic candidates for demyelinating diseases. Funding This work was supported by the Jürgen Manchot Foundation, Düsseldorf; Research Commission of the Medical Faculty of Heinrich-Heine-University Düsseldorf; Christiane and Claudia Hempel Foundation; Stifterverband/Novartisstiftung; James and Elisabeth Cloppenburg, Peek and Cloppenburg Düsseldorf Stiftung and International Progressive MS Alliance (BRAVEinMS).

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Section: Methodsmentioning

confidence: 99%

Identification of novel myelin repair drugs by modulation of oligodendroglial differentiation competence

et al. 2021

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“…Interestingly, in experiments using hamsters the cuprizone concentration needed to be increased to 3% or even 5%—compared to 0.2%—0.5% in experiments on mice or rat—to induce brain alterations. One very small study using non-human primates did not find brain demyelination in young cynomolgus macaques even after 18 weeks on a 3% cuprizone diet [ 38 ]. However, the lack of demyelination could be because even higher, but untested, doses of cuprizone are needed to induce demyelination in macaques.…”

Section: Main Textmentioning

confidence: 99%

Oligodendrocyte death and myelin loss in the cuprizone model: an updated overview of the intrinsic and extrinsic causes of cuprizone demyelination

Zirngibl

Assinck

Sizov

et al. 2022

Mol Neurodegeneration

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Background The dietary consumption of cuprizone – a copper chelator – has long been known to induce demyelination of specific brain structures and is widely used as model of multiple sclerosis. Despite the extensive use of cuprizone, the mechanism by which it induces demyelination are still unknown. With this review we provide an updated understanding of this model, by showcasing two distinct yet overlapping modes of action for cuprizone-induced demyelination; 1) damage originating from within the oligodendrocyte, caused by mitochondrial dysfunction or reduced myelin protein synthesis. We term this mode of action ‘intrinsic cell damage’. And 2) damage to the oligodendrocyte exerted by inflammatory molecules, brain resident cells, such as oligodendrocytes, astrocytes, and microglia or peripheral immune cells – neutrophils or T-cells. We term this mode of action ‘extrinsic cellular damage’. Lastly, we summarize recent developments in research on different forms of cell death induced by cuprizone, which could add valuable insights into the mechanisms of cuprizone toxicity. With this review we hope to provide a modern understanding of cuprizone-induced demyelination to understand the causes behind the demyelination in MS.

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“…The following primary antibodies were used: mouse anti-APC (CC1, 1:300, Sigma-Aldrich, Cat# OP80, RRID:AB_ 2057371); rabbit anti-sex determining region Y-Box 10 (Sox10; 1:100, DCS Immunoline, Hamburg, Germany Cat# S1058C002, RRID: AB_2313583) and goat anti-Sox10 (1:200, R&D System, Minneapolis, US Cat# AF2864; RRID: AB_442208); rat anti-proteolipid protein (PLP, 1:250, kind gift from B. Trapp and R. Dutta, Dept. of Neurosciences, Cleveland Clinic, OH, [ 22 ]), mouse anti-mammalian Achaete scute homolog-1 (Mash1, 1:200; [ 23 , 24 ]) and rabbit anti-mitochondrial outer membrane marker (Tom20; Santa Cruz, Heidelberg, Germany Cat# sc-11415 (FL-145), RRID: AB_2207533). Slices were then washed twice in 1 × TBS for 5 min each and secondary antibodies were diluted 1:200 and applied for 30 min along with 4′,6-diamidino-2-phenylindol (DAPI, 1:50) in PBS.…”

Section: Methodsmentioning

confidence: 99%

Teriflunomide as a therapeutic means for myelin repair

Göttle

Groh

Reiche

et al. 2023

J Neuroinflammation

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Background Promotion of myelin repair in the context of demyelinating diseases such as multiple sclerosis (MS) still represents a clinical unmet need, given that this disease is not only characterized by autoimmune activities but also by impaired regeneration processes. Hence, this relates to replacement of lost oligodendrocytes and myelin sheaths—the primary targets of autoimmune attacks. Endogenous remyelination is mainly mediated via activation and differentiation of resident oligodendroglial precursor cells (OPCs), whereas its efficiency remains limited and declines with disease progression and aging. Teriflunomide has been approved as a first-line treatment for relapsing remitting MS. Beyond its role in acting via inhibition of de novo pyrimidine synthesis leading to a cytostatic effect on proliferating lymphocyte subsets, this study aims to uncover its potential to foster myelin repair. Methods Within the cuprizone mediated de-/remyelination model teriflunomide dependent effects on oligodendroglial homeostasis and maturation, related to cellular processes important for myelin repair were analyzed in vivo. Teriflunomide administration was performed either as pulse or continuously and markers specific for oligodendroglial maturation and mitochondrial integrity were examined by means of gene expression and immunohistochemical analyses. In addition, axon myelination was determined using electron microscopy. Results Both pulse and constant teriflunomide treatment efficiently boosted myelin repair activities in this model, leading to accelerated generation of oligodendrocytes and restoration of myelin sheaths. Moreover, teriflunomide restored mitochondrial integrity within oligodendroglial cells. Conclusions The link between de novo pyrimidine synthesis inhibition, oligodendroglial rescue, and maintenance of mitochondrial homeostasis appears as a key for successful myelin repair and hence for protection of axons from degeneration.

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Cuprizone does not induce CNS demyelination in nonhuman primates

Cited by 10 publications

References 17 publications

Identification of novel myelin repair drugs by modulation of oligodendroglial differentiation competence

Identification of novel myelin repair drugs by modulation of oligodendroglial differentiation competence

Oligodendrocyte death and myelin loss in the cuprizone model: an updated overview of the intrinsic and extrinsic causes of cuprizone demyelination

Teriflunomide as a therapeutic means for myelin repair

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