Teriflunomide as a therapeutic means for myelin repair

Abstract

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.

Polysialic acid promotes remyelination in cerebellar slice cultures by Siglec-E-dependent modulation of microglia polarization

“…There have been many successes in the treatment of MS, but so far all licensed therapeutics aim to modulate the peripheral immune system (Baecher-Allan et al, 2018 ; Derfuss et al, 2020 ). Some experimental approaches have addressed remyelination in MS (Gingele and Stangel, 2020 ); however, no treatment addresses microglia specifically, although there are suggestions that drugs such as teriflunomide may, in addition to the effect on lymphocytes, modulate oligodendrocytes and microglia (Wostradowski et al, 2016 ; Göttle et al, 2023 ). Direct modulation of microglia may be an attractive approach to support endogenous myelin repair by an additional mode of action combined with the immunomodulation of the peripheral immune system.…”

Sex differences in the neuronal transcriptome and synaptic mitochondrial function in the cerebral cortex of a multiple sclerosis model

“…Quantitative analysis of mitochondrial morphology was conducted using the Mitochondria analyzer plugin for ImageJ (52,53). 4 The plugin's thresholding settings were adjusted as follows: subtract background at 1.25, sigma filter plus at 2, enhance local contrast at 1.4, and block size at 1.05 with a C-value of 11.…”