Anti-inflammatory and remyelinating effects of fexagratinib in experimental multiple sclerosis.

IF 6.8 2区 医学 Q1 PHARMACOLOGY & PHARMACY British Journal of Pharmacology Pub Date : 2024-10-05 DOI:10.1111/bph.17341
Fynn Gurski, Kian Shirvanchi, Vinothkumar Rajendran, Ranjithkumar Rajendran, Fevronia-Foivi Megalofonou, Gregor Böttiger, Christine Stadelmann, Sudhanshu Bhushan, Süleyman Ergün, Srikanth Karnati, Martin Berghoff
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Abstract

Background and purpose: FGF, VEGFR-2 and CSF1R signalling pathways play a key role in the pathogenesis of multiple sclerosis (MS). Selective inhibition of FGFR by infigratinib in MOG35-55-induced experimental autoimmune encephalomyelitis (EAE) prevented severe first clinical episodes by 40%; inflammation and neurodegeneration were reduced, and remyelination was enhanced. Multi-kinase inhibition of FGFR1-3, CSFR and VEGFR-2 by fexagratinib (formerly known as AZD4547) may be more efficient in reducing inflammation, neurodegeneration and regeneration in the disease model.

Experimental approach: Female C57BL/6J mice were treated with fexagratinib (6.25 or 12.5 mg·kg-1) orally or placebo over 10 days either from time of EAE induction (prevention experiment) or onset of symptoms (suppression experiment). Effects on inflammation, neurodegeneration and remyelination were assessed at the peak of the disease (Day 18/20 post immunization) and the chronic phase of EAE (Day 41/42).

Key results: In the prevention experiment, treatment with 6.25 or 12.5 mg·kg-1 fexagratinib prevented severe first clinical episodes by 66.7% or 84.6% respectively. Mice treated with 12.5 mg·kg-1 fexagratinib hardly showed any symptoms in the chronic phase of EAE. In the suppression experiment, fexagratinib resulted in a long-lasting reduction of severe symptoms by 91 or 100%. Inflammation and demyelination were reduced, and axonal density, numbers of oligodendrocytes and their precursor cells, and remyelinated axons were increased by both experimental approaches.

Conclusion and implications: Multi-kinase inhibition by fexagratinib in a well-tolerated dose of 1 mg·kg-1 in humans may be a promising approach to reduce inflammation and neurodegeneration, to slow down disease progression and support remyelination in patients.

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非加替尼在实验性多发性硬化症中的抗炎和再髓鞘作用
背景和目的:FGF、VEGFR-2和CSF1R信号通路在多发性硬化症(MS)的发病机制中起着关键作用。在 MOG35-55 诱导的实验性自身免疫性脑脊髓炎(EAE)中,英夫拉替尼选择性抑制 FGFR,可使首次临床发作的严重程度降低 40%;炎症和神经变性减轻,髓鞘再形成增强。通过fexagratinib(原名AZD4547)对FGFR1-3、CSFR和VEGFR-2的多激酶抑制可能更有效地减少疾病模型中的炎症、神经变性和再生:实验方法:雌性 C57BL/6J 小鼠从诱发 EAE(预防实验)或出现症状(抑制实验)开始,口服 fexagratinib(6.25 或 12.5 mg-kg-1)或安慰剂 10 天。在疾病高峰期(免疫后第18/20天)和EAE慢性期(第41/42天)评估了对炎症、神经变性和再髓鞘化的影响:在预防实验中,用6.25或12.5 mg-kg-1 fexagratinib治疗小鼠,可使首次临床发作的严重程度分别降低66.7%和84.6%。接受12.5 mg-kg-1 fexagratinib治疗的小鼠在EAE慢性期几乎没有出现任何症状。在抑制实验中,fexagratinib可使严重症状长期减轻91%或100%。两种实验方法都能减少炎症和脱髓鞘,增加轴突密度、少突胶质细胞及其前体细胞数量和再髓鞘化轴突:在人体中使用耐受性良好的1毫克-千克-1剂量的fexagratinib多激酶抑制剂可能是减少炎症和神经退行性变、延缓疾病进展和支持患者再髓鞘化的一种很有前景的方法。
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来源期刊
CiteScore
15.40
自引率
12.30%
发文量
270
审稿时长
2.0 months
期刊介绍: The British Journal of Pharmacology (BJP) is a biomedical science journal offering comprehensive international coverage of experimental and translational pharmacology. It publishes original research, authoritative reviews, mini reviews, systematic reviews, meta-analyses, databases, letters to the Editor, and commentaries. Review articles, databases, systematic reviews, and meta-analyses are typically commissioned, but unsolicited contributions are also considered, either as standalone papers or part of themed issues. In addition to basic science research, BJP features translational pharmacology research, including proof-of-concept and early mechanistic studies in humans. While it generally does not publish first-in-man phase I studies or phase IIb, III, or IV studies, exceptions may be made under certain circumstances, particularly if results are combined with preclinical studies.
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