The <i>Xenopus</i> tadpole: An in vivo model to screen drugs favoring remyelination

Mannioui, Abdelkrim; Vauzanges, Quentin; Fini, Jean-Baptiste; Henriet, Esther; Sekizar, S.; Azoyan, Loris; Thomas, Jean Léon; Pasquier, David Du; Giovannangéli, Carine; Demeneix, Barbara; Lubetzki, Catherine; Zalc, Bernard

doi:10.1177/1352458517721355

Cited by 51 publications

(67 citation statements)

References 36 publications

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“…Enhanced remyelination was observed with siponimod under functional antagonist conditions using an in vivo Xenopus tadpole model [116]. Following induced demyelination, a marked increase in myelinated fibres was observed with siponimod compared with the spontaneous remyelination control.…”

Section: Effects On Remyelination and Repairmentioning

confidence: 89%

“…Following induced demyelination, a marked increase in myelinated fibres was observed with siponimod compared with the spontaneous remyelination control. Remyelination was improved by a selective S1PR 5 agonist, but not by a selective S1PR 1 agonist, and siponimod was ineffective following deletion of S1PR 5 by gene editing, indicating the importance of S1PR 5 in the promyelinating effects of siponimod [116].…”

Section: Effects On Remyelination and Repairmentioning

confidence: 95%

“…Interaction of fingolimod and siponimod with S1PR 5 on oligodendrocytes has been associated with protection against demyelination and the promotion of remyelination in both in vitro and in vivo animal studies [77,99,[114][115][116]. A cell culture study showed that, following demyelination, fingolimod exposure was associated with increases in the biochemical and morphological markers of remyelination [114].…”

Section: Effects On Remyelination and Repairmentioning

confidence: 99%

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Sphingosine 1-phosphate Receptor Modulator Therapy for Multiple Sclerosis: Differential Downstream Receptor Signalling and Clinical Profile Effects

Chun

Giovannoni

Hunter

2020

Drugs

103

146

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Lysophospholipids are a class of bioactive lipid molecules that produce their effects through various G protein-coupled receptors (GPCRs). Sphingosine 1-phosphate (S1P) is perhaps the most studied lysophospholipid and has a role in a wide range of physiological and pathophysiological events, via signalling through five distinct GPCR subtypes, S1PR 1 to S1PR 5 . Previous and continuing investigation of the S1P pathway has led to the approval of three S1PR modulators, fingolimod, siponimod and ozanimod, as medicines for patients with multiple sclerosis (MS), as well as the identification of new S1PR modulators currently in clinical development, including ponesimod and etrasimod. S1PR modulators have complex effects on S1PRs, in some cases acting both as traditional agonists as well as agonists that produce functional antagonism. S1PR subtype specificity influences their downstream effects, including aspects of their benefit:risk profile. Some S1PR modulators are prodrugs, which require metabolic modification such as phosphorylation via sphingosine kinases, resulting in different pharmacokinetics and bioavailability, contrasting with others that are direct modulators of the receptors. The complex interplay of these characteristics dictates the clinical profile of S1PR modulators. This review focuses on the S1P pathway, the characteristics and S1PR binding profiles of S1PR modulators, the mechanisms of action of S1PR modulators with regard to immune cell trafficking and neuroprotection in MS, together with a summary of the clinical effectiveness of the S1PR modulators that are approved or in late-stage development for patients with MS. Electronic supplementary material The online version of this article (10.1007/s40265-020-01431-8) contains supplementary material, which is available to authorized users.

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Section: Effects On Remyelination and Repairmentioning

confidence: 89%

Section: Effects On Remyelination and Repairmentioning

confidence: 95%

Section: Effects On Remyelination and Repairmentioning

confidence: 99%

See 1 more Smart Citation

Sphingosine 1-phosphate Receptor Modulator Therapy for Multiple Sclerosis: Differential Downstream Receptor Signalling and Clinical Profile Effects

Chun

Giovannoni

Hunter

2020

Drugs

103

146

View full text Add to dashboard Cite

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“…Finally, it should be noted that S1Pr5 is also expressed by oligodendrocytes and their progenitor cells [121,130,131] and may, therefore, modify myelin repair (i.e., remyelination) but may also promote oligodendrocyte survival in an inflammatory environment. While the relevance of fingolimod for remyelination has been discussed in detail elsewhere [132], we consider it important to note that siponimod [133] was one of the most efficient substances in a Xenopus in vivo model among a range of molecules tested that favored remyelination. However, future studies with more complex organisms will be needed to test the potential remyelination function of siponimod.…”

Section: From Fty720 To Siponimodmentioning

confidence: 89%

Does Siponimod Exert Direct Effects in the Central Nervous System?

Kipp

2020

Cells

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The modulation of the sphingosine 1-phosphate receptor is an approved treatment for relapsing multiple sclerosis because of its anti-inflammatory effect of retaining lymphocytes in lymph nodes. Different sphingosine 1-phosphate receptor subtypes are expressed in the brain and spinal cord, and their pharmacological effects may improve disease development and neuropathology. Siponimod (BAF312) is a novel sphingosine 1-phosphate receptor modulator that has recently been approved for the treatment of active secondary progressive multiple sclerosis (MS). In this review article, we summarize recent evidence suggesting that the active role of siponimod in patients with progressive MS may be due to direct interaction with central nervous system cells. Additionally, we tried to summarize our current understanding of the function of siponimod and discuss the effects observed in the case of MS.

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“…23 Siponimod does not influence the S1P 3 such as fingolimod, which is mainly responsible for adverse cardiac effects such as bradycardia. 24 In a model of demyelination in Xenopus tadpoles, treatment with siponimod leads to strong remyelination, 25 suggesting that the medication might be effective in progressive forms of MS. Siponimod reduces the release of IL-6 in TNFα/IL17 activated microglia in vitro and has protective effects on demyelination in LPCmediated demyelination in organotypic slice cultures. 26 Siponimod has positive effects on the clinical course of EAE in C57BL6 mice, in accordance with reduced astrogliosis and microgliosis.…”

Section: Targeting the Sphingosine-1-phosphate Receptormentioning

confidence: 99%

Progressive multiple sclerosis: latest therapeutic developments and future directions

Faissner

Gold

2019

Ther Adv Neurol Disord

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Multiple sclerosis (MS) is a chronic inflammatory condition of the central nervous system leading to demyelination and neurodegeneration. While the initial presentation is mostly characterized by a relapsing–remitting disease, patients often progress naturally after 10–15 years to a secondary-progressive disease course. Another 10–15% present with an initial, primary-progressive MS course. Pathogenic mechanisms possibly driving progression include continued compartmentalized inflammation by T- and B-lymphocytes and cells of innate immunity, oxidative stress, iron accumulation, and consecutive mitochondrial damage, altogether leading to neurodegeneration with accumulation of disability. Increasing knowledge about pathogenic mechanisms involved in progressive MS helps to design more specific and precise therapeutic approaches. Successful examples are the B-cell targeting monoclonal antibody ocrelizumab, effective in primary progressive MS, and the sphingosine-1-receptor modulator siponimod, effective in active forms of secondary-progressive MS. Apart from that, other medications such as the B-cell targeted antibody ofatumumab, cladribine due to T- and B-cell depletion, and other sphingosine-1-receptor modulators such as ozanimod and ponesimod are under development. Moreover, some therapeutic approaches in preclinical stages are under development. In this review, we will summarize the newest therapeutic development in the field of progressive MS of the last 3 years, and shed light on auspicious substances with similar mechanisms and new developments in the therapeutic pipeline, presumably supporting a bright future for progressive MS treatment.

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The Xenopus tadpole: An in vivo model to screen drugs favoring remyelination

Abstract: This Xenopus transgenic line constitutes a simple in vivo screening platform for myelin repair therapeutics. We validated several known promyelinating compounds and demonstrated that the strong remyelinating efficacy of siponimod implicates the sphingosine-1-phosphate receptor 5.

Cited by 51 publications

References 36 publications

Sphingosine 1-phosphate Receptor Modulator Therapy for Multiple Sclerosis: Differential Downstream Receptor Signalling and Clinical Profile Effects

Sphingosine 1-phosphate Receptor Modulator Therapy for Multiple Sclerosis: Differential Downstream Receptor Signalling and Clinical Profile Effects

Does Siponimod Exert Direct Effects in the Central Nervous System?

Progressive multiple sclerosis: latest therapeutic developments and future directions

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