Gurski Fynn, Shirvanchi Kian, Rajendran Vinothkumar, Rajendran Ranjithkumar, Megalofonou Fevronia-Foivi, Böttiger Gregor, Stadelmann Christine, Bhushan Sudhanshu, Ergün Süleyman, Karnati Srikanth, Berghoff Martin
Experimental Neurology, Department of Neurology, University of Giessen, Giessen, Germany.
Institute of Neuropathology, University Medical Centre Göttingen, Göttingen, Germany.
Br J Pharmacol. 2025 Jan;182(1):142-161. doi: 10.1111/bph.17341. Epub 2024 Oct 5.
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 MOG-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.
Female C57BL/6J mice were treated with fexagratinib (6.25 or 12.5 mg·kg) 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).
In the prevention experiment, treatment with 6.25 or 12.5 mg·kg fexagratinib prevented severe first clinical episodes by 66.7% or 84.6% respectively. Mice treated with 12.5 mg·kg 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.
Multi-kinase inhibition by fexagratinib in a well-tolerated dose of 1 mg·kg in humans may be a promising approach to reduce inflammation and neurodegeneration, to slow down disease progression and support remyelination in patients.
成纤维细胞生长因子（FGF）、血管内皮生长因子受体-2（VEGFR-2）和集落刺激因子1受体（CSF1R）信号通路在多发性硬化症（MS）的发病机制中起关键作用。在髓鞘少突胶质细胞糖蛋白（MOG）诱导的实验性自身免疫性脑脊髓炎（EAE）中，因非格司他尼选择性抑制成纤维细胞生长因子受体（FGFR）可使严重的首次临床发作减少40%；炎症和神经退行性变减轻，髓鞘再生增强。非格司他尼（原名AZD4547）对FGFR1-3、集落刺激因子受体（CSFR）和VEGFR-2的多激酶抑制作用在该疾病模型中可能在减轻炎症、神经退行性变和促进再生方面更有效。
雌性C57BL/6J小鼠在EAE诱导时（预防实验）或症状出现时（抑制实验），连续10天口服非格司他尼（6.25或12.5mg·kg）或安慰剂。在疾病高峰期（免疫后第18/20天）和EAE慢性期（第41/42天）评估对炎症、神经退行性变和髓鞘再生的影响。
在预防实验中，6.25或12.5mg·kg非格司他尼治疗分别使严重的首次临床发作减少66.7%或84.6%。用12.5mg·kg非格司他尼治疗的小鼠在EAE慢性期几乎未出现任何症状。在抑制实验中，非格司他尼使严重症状长期减少91%或100%。两种实验方法均使炎症和脱髓鞘减轻，轴突密度、少突胶质细胞及其前体细胞数量以及髓鞘再生轴突增加。
非格司他尼以人体中耐受良好的剂量1mg·kg进行多激酶抑制，可能是减轻炎症和神经退行性变、减缓疾病进展以及支持患者髓鞘再生的一种有前景的方法。
