Tofacitinib enhances remyelination and improves myelin integrity in cuprizone-induced mice

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Gunaydin C., Önger M. E., Avcı B., Bozkurt A., Terzi M., Bilge S. S.

IMMUNOPHARMACOLOGY AND IMMUNOTOXICOLOGY, cilt.43, sa.6, ss.790-798, 2021 (SCI-Expanded) identifier identifier identifier

  • Yayın Türü: Makale / Tam Makale
  • Cilt numarası: 43 Sayı: 6
  • Basım Tarihi: 2021
  • Doi Numarası: 10.1080/08923973.2021.1986063
  • Dergi Adı: IMMUNOPHARMACOLOGY AND IMMUNOTOXICOLOGY
  • Derginin Tarandığı İndeksler: Science Citation Index Expanded (SCI-EXPANDED), Scopus, Academic Search Premier, Aquatic Science & Fisheries Abstracts (ASFA), BIOSIS, CAB Abstracts, EMBASE, Food Science & Technology Abstracts, MEDLINE, Veterinary Science Database
  • Sayfa Sayıları: ss.790-798
  • Anahtar Kelimeler: Tofacitinib, cuprizone, JAK, STAT, demyelination, remyelination, MULTIPLE-SCLEROSIS, INHIBITOR TOFACITINIB, JAK/STAT PATHWAY, JAK INHIBITOR, MMP-9, DEMYELINATION, PATHOGENESIS, CYTOKINES, MODELS
  • Ondokuz Mayıs Üniversitesi Adresli: Evet

Özet

Aim Demyelination and subsequent remyelination are well-known mechanisms in multiple sclerosis (MS) pathology. Current research mainly focused on preventing demyelination or regulating the peripheral immune system to protect further damage to the central nervous system. However, information about another essential mechanism, remyelination, and its balance of the immune response within the central nervous system's boundaries is still limited. Materials and methods In this study, we tried to demonstrate the effect of the recently introduced Janus kinase (JAK)-signal transducer and activator of transcription (STAT) inhibitor, tofacitinib, on remyelination.Demyelination was induced by 6-week cuprizone administration, followed by 2-week tofacitinib (10, 30, and 100 mg/kg) treatment. Results At the functional level, tofacitinib improved cuprizone-induced decline in motor coordination and muscle strength, which were assessed by rotarod and hanging wire tests. Tofacitinib also showed anti-inflammatory effect by alleviating the cuprizone-induced increase in the central levels of interferon-gamma (IFN-gamma), interleukin (IL)-6, IL-1 beta, and tumor necrosis alpha (TNF-alpha). Furthermore, tofacitinib also suppressed the cuprizone-induced increase in matrix metalloproteinases (MMP)-9 and MMP-2 levels. Additionally, cuprizone-induced loss of myelin integrity and myelin basic protein expression was inhibited by tofacitinib. At the molecular level, we also assessed phosphorylation of STAT-3 and STAT-5, and our data indicates tofacitinib suppressed cuprizone-induced phosphorylation in those proteins. Conclusion Our study highlights JAK/STAT inhibition provides beneficial effects on remyelination via inhibition of inflammatory cascade.