A novel fumarate, isosorbide di-(methyl fumarate) (IDMF), replicates astrocyte transcriptome responses to dimethyl fumarate (DMF) but specifically down-regulates genes linked to a reactive phenotype

William R. Swindell, Krzysztof Bojanowski, Ratan K. Chaudhuri

Research output: Contribution to journalArticlepeer-review

6 Scopus citations

Abstract

Dimethyl fumarate (DMF) has emerged as a first-line treatment for the relapsing-remitting multiple sclerosis (RRMS) subtype. It is hypothesized that DMF has anti-inflammatory and antioxidant effects although mechanisms are not fully understood. This study used RNA-seq to profile gene expression responses to DMF in cultured astrocytes. Responses were compared with those of isosorbide di-(methyl fumarate) (IDMF), a newly designed fumarate that may partially replicate DMF activity with fewer adverse effects. Both compounds altered the expression of MS-associated genes, including those near MS susceptibility loci and genes dysregulated in MS patient astrocytes. The shared DMF/IDMF transcriptome response involved altered expression of antioxidant genes (e.g., HMOX1) and genes linked to extracellular matrix integrity (TIMP3, MMP9) and migration of pro-inflammatory cells into CNS (CCL2). IDMF-specific transcriptome responses included down-regulation of mitotic genes associated with a proliferative reactive astrocyte phenotype (ICAM1) and repression of genes encoding NF-kappaB subunits (NFKB2, RELA, RELB) and NF-kappaB targets (NCAPG, CXCL1, OAS3). Overall, these results identify astrocyte-centered mechanisms that may contribute to the established efficacy of DMF as an RRMS treatment. Furthermore, our findings support a rationale for further studies of IDMF as a novel fumarate, which may have unique suppressive effects on astrocyte reactivity and glial scar formation. [200 words].

Original languageEnglish (US)
Pages (from-to)475-481
Number of pages7
JournalBiochemical and Biophysical Research Communications
Volume532
Issue number3
DOIs
StatePublished - Nov 12 2020
Externally publishedYes

Keywords

  • Astrocyte
  • Dimethyl fumarate
  • Isosorbide di-(methyl fumarate)
  • Multiple sclerosis
  • NF-kappaB
  • NRF-2
  • RNA-seq

ASJC Scopus subject areas

  • Biophysics
  • Biochemistry
  • Molecular Biology
  • Cell Biology

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