Swindell William R, Bojanowski Krzysztof, Chaudhuri Ratan K
Department of Internal Medicine, The Jewish Hospital, Cincinnati, OH 45236, USA.
Sunny BioDiscovery Inc., Santa Paula, CA 93060, USA.
Pharmaceuticals (Basel). 2022 Apr 11;15(4):461. doi: 10.3390/ph15040461.
Dimethyl fumarate (DMF) has emerged as a first-line therapy for relapsing-remitting multiple sclerosis (RRMS). This treatment, however, has been limited by adverse effects, which has prompted development of novel derivatives with improved tolerability. We compared the effects of fumarates on gene expression in astrocytes. Our analysis included diroximel fumarate (DRF) and its metabolite monomethyl fumarate (MMF), along with a novel compound isosorbide di-(methyl fumarate) (IDMF). Treatment with IDMF resulted in the largest number of differentially expressed genes. The effects of DRF and MMF were consistent with NRF2 activation and NF-κB inhibition, respectively. IDMF responses, however, were concordant with both NRF2 activation and NF-κB inhibition, and we confirmed IDMF-mediated NF-κB inhibition using a reporter assay. IDMF also down-regulated expression and IDMF-decreased gene promoters were enriched with IRF1 recognition sequences. Genes altered by each fumarate overlapped significantly with those near loci from MS genetic association studies, but IDMF had the strongest overall effect on MS-associated genes. These results show that next-generation fumarates, such as DRF and IDMF, have effects differing from those of the MMF metabolite. Our findings support a model in which IDMF attenuates oxidative stress via NRF2 activation, with suppression of NF-κB and IRF1 contributing to mitigation of inflammation and pyroptosis.
富马酸二甲酯（DMF）已成为复发缓解型多发性硬化症（RRMS）的一线治疗药物。然而，这种治疗方法受到不良反应的限制，这促使人们开发耐受性更好的新型衍生物。我们比较了富马酸盐对星形胶质细胞基因表达的影响。我们的分析包括二氧ximel富马酸盐（DRF）及其代谢物单甲基富马酸盐（MMF），以及一种新型化合物异山梨醇二（甲基富马酸盐）（IDMF）。用IDMF处理导致差异表达基因的数量最多。DRF和MMF的作用分别与NRF2激活和NF-κB抑制一致。然而，IDMF的反应与NRF2激活和NF-κB抑制均一致，并且我们使用报告基因测定法证实了IDMF介导的NF-κB抑制。IDMF还下调了表达，并且IDMF降低的基因启动子富含IRF1识别序列。每种富马酸盐改变的基因与MS遗传关联研究中位点附近的基因有显著重叠，但IDMF对MS相关基因的总体影响最强。这些结果表明，下一代富马酸盐，如DRF和IDMF，具有与MMF代谢物不同的作用。我们的研究结果支持一种模型，其中IDMF通过激活NRF2减轻氧化应激，同时抑制NF-κB和IRF1有助于减轻炎症和焦亡。
