Teriflunomide as a therapeutic means for myelin repair

Journal of Neuroinflammation

Research

Annika Zink¹  Alessandro Prigione¹  Patrick Küry²  Iria Samper Agrelo²  Rainer Akkermann²  Peter Göttle²  Laura Reiche²  Joel Gruchot²  Nicole Rychlik²  Luisa Werner²  Hans-Peter Hartung³  Janos Groh⁴  Rudolf Martini⁴ 

[1] Department of General Pediatrics, Neonatology and Pediatric Cardiology, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany;Department of Neurology, Medical Faculty, Heinrich-Heine-University, Moorenstrasse 5, 40225, Düsseldorf, Germany;Department of Neurology, Medical Faculty, Heinrich-Heine-University, Moorenstrasse 5, 40225, Düsseldorf, Germany;Brain and Mind Center, University of Sydney, Sydney, Australia;Department of Neurology, Palacky University Olomouc, Olomouc, Czech Republic;Department of Neurology, Section of Developmental Neurobiology, University Hospital, Würzburg, Germany;

关键词: Multiple sclerosis;    Teriflunomide;    Oligodendrocyte;    Remyelination;    Neuroregeneration;   

DOI  :  10.1186/s12974-022-02686-6

 received in 2022-09-16, accepted in 2022-12-23,  发布年份 2022

来源: Springer

【 摘 要 】

BackgroundPromotion 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.MethodsWithin 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.ResultsBoth 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.ConclusionsThe 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.

【 授权许可】

CC BY   
© The Author(s) 2023

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