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.

Brain and Mind Center University of Sydney Sydney Australia

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 Palacky University Olomouc Olomouc Czech Republic

Department of Neurology Section of Developmental Neurobiology University Hospital Würzburg Germany

000      

00000naa a2200000 a 4500

001      

bmc23004640

003      

CZ-PrNML

005      

20230425171634.0

007      

ta

008      

230418s2023 enk f 000 0|eng||

009      

AR

024    7_

$a 10.1186/s12974-022-02686-6 $2 doi

035    __

$a (PubMed)36611185

040    __

$a ABA008 $b cze $d ABA008 $e AACR2

041    0_

$a eng

044    __

$a enk

100    1_

$a Göttle, Peter $u Department of Neurology, Medical Faculty, Heinrich-Heine-University, Moorenstrasse 5, 40225, Düsseldorf, Germany

245    10

$a Teriflunomide as a therapeutic means for myelin repair / $c P. Göttle, J. Groh, L. Reiche, J. Gruchot, N. Rychlik, L. Werner, I. Samper Agrelo, R. Akkermann, A. Zink, A. Prigione, HP. Hartung, R. Martini, P. Küry

520    9_

$a 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.

650    12

$a myelinová pochva $x metabolismus $7 D009186

650    12

$a oligodendroglie $x metabolismus $7 D009836

650    _2

$a krotonáty $x farmakologie $x terapeutické užití $7 D003437

650    _2

$a hydroxybutyráty $x metabolismus $x farmakologie $7 D006885

650    _2

$a buněčná diferenciace $7 D002454

655    _2

$a časopisecké články $7 D016428

700    1_

$a Groh, Janos $u Department of Neurology, Section of Developmental Neurobiology, University Hospital, Würzburg, Germany

700    1_

$a Reiche, Laura $u Department of Neurology, Medical Faculty, Heinrich-Heine-University, Moorenstrasse 5, 40225, Düsseldorf, Germany

700    1_

$a Gruchot, Joel $u Department of Neurology, Medical Faculty, Heinrich-Heine-University, Moorenstrasse 5, 40225, Düsseldorf, Germany

700    1_

$a Rychlik, Nicole $u Department of Neurology, Medical Faculty, Heinrich-Heine-University, Moorenstrasse 5, 40225, Düsseldorf, Germany

700    1_

$a Werner, Luisa $u Department of Neurology, Medical Faculty, Heinrich-Heine-University, Moorenstrasse 5, 40225, Düsseldorf, Germany

700    1_

$a Samper Agrelo, Iria $u Department of Neurology, Medical Faculty, Heinrich-Heine-University, Moorenstrasse 5, 40225, Düsseldorf, Germany

700    1_

$a Akkermann, Rainer $u Department of Neurology, Medical Faculty, Heinrich-Heine-University, Moorenstrasse 5, 40225, Düsseldorf, Germany

700    1_

$a Zink, Annika $u Department of General Pediatrics, Neonatology and Pediatric Cardiology, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany

700    1_

$a Prigione, Alessandro $u Department of General Pediatrics, Neonatology and Pediatric Cardiology, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany

700    1_

$a Hartung, Hans-Peter $u Department of Neurology, Medical Faculty, Heinrich-Heine-University, Moorenstrasse 5, 40225, Düsseldorf, Germany $u Brain and Mind Center, University of Sydney, Sydney, Australia $u Department of Neurology, Palacky University Olomouc, Olomouc, Czech Republic

700    1_

$a Martini, Rudolf $u Department of Neurology, Section of Developmental Neurobiology, University Hospital, Würzburg, Germany

700    1_

$a Küry, Patrick $u Department of Neurology, Medical Faculty, Heinrich-Heine-University, Moorenstrasse 5, 40225, Düsseldorf, Germany. kuery@uni-duesseldorf.de

773    0_

$w MED00163330 $t Journal of neuroinflammation $x 1742-2094 $g Roč. 20, č. 1 (2023), s. 7

856    41

$u https://pubmed.ncbi.nlm.nih.gov/36611185 $y Pubmed

910    __

$a ABA008 $b sig $c sign $y p $z 0

990    __

$a 20230418 $b ABA008

991    __

$a 20230425171630 $b ABA008

999    __

$a ok $b bmc $g 1924996 $s 1190849

BAS    __

$a 3

BAS    __

$a PreBMC-MEDLINE

BMC    __

$a 2023 $b 20 $c 1 $d 7 $e 20230107 $i 1742-2094 $m Journal of neuroinflammation $n J Neuroinflammation $x MED00163330

LZP    __

$a Pubmed-20230418