TY - JOUR
T1 - 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
AU - Swindell, William R.
AU - Bojanowski, Krzysztof
AU - Chaudhuri, Ratan K.
N1 - Funding Information:
The authors thank Synthon, Ltd. (Boonton, NJ, USA) for funding this research and Dr. Tony Chang (International Chemistry Testing, Milford, MA), Stephanie Ma (Sunny BioDiscovery, Santa Paula, CA), Pedro Corona (Sunny BioDiscovery), and Geovani Quijas (Sunny BioDiscovery) for their dedicated assistance.
Publisher Copyright:
© 2020 Elsevier Inc.
PY - 2020/11/12
Y1 - 2020/11/12
N2 - 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].
AB - 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].
KW - Astrocyte
KW - Dimethyl fumarate
KW - Isosorbide di-(methyl fumarate)
KW - Multiple sclerosis
KW - NF-kappaB
KW - NRF-2
KW - RNA-seq
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U2 - 10.1016/j.bbrc.2020.08.079
DO - 10.1016/j.bbrc.2020.08.079
M3 - Article
C2 - 32892947
AN - SCOPUS:85090313182
SN - 0006-291X
VL - 532
SP - 475
EP - 481
JO - Biochemical and Biophysical Research Communications
JF - Biochemical and Biophysical Research Communications
IS - 3
ER -