title: Pharmacodynamics of Dimethyl Fumarate Are Tissue Specific and Involve NRF2-Dependent and -Independent Mechanisms.
abstract: Gastro-resistant dimethyl fumarate (DMF) is an oral therapeutic indicated for the treatment of relapsing multiple sclerosis. Recent data suggest that a primary pharmacodynamic response to DMF treatment is activation of the nuclear factor (erythroid-derived 2)-like 2 (NRF2) pathway; however, the gene targets modulated downstream of NRF2 that contribute to DMF-dependent effects are poorly understood.
  
  
  
  Using wild-type and NRF2 knockout mice, we characterized DMF transcriptional responses throughout the brain and periphery to understand DMF effects in vivo and to explore the necessity of NRF2 in this process. Our findings identified tissue-specific expression of NRF2 target genes as well as NRF2-dependent and -independent gene regulation after DMF administration. Furthermore, using gene ontology, we identified common biological pathways that may be regulated by DMF and contribute to in vivo functional effects.
  
  
  
  Together, these data suggest that DMF modulates transcription through multiple pathways, which has implications for the cytoprotective, immunomodulatory, and clinical properties of DMF.
  
  
  
  These findings provide further understanding of the DMF mechanism of action and propose potential therapeutic targets that warrant further investigation for treating neurodegenerative diseases. Antioxid. Redox Signal. 24, 1058-1071.
authors.affiliation: 1 Neurology Research, Biogen, Inc., Cambridge, Massachusetts.|2 GPN, Boston University School of Medicine , Boston, Massachusetts.
authors.forename: Melanie S
authors.initials: MS
authors.lastname: Brennan
authors.affiliation: 1 Neurology Research, Biogen, Inc., Cambridge, Massachusetts.
authors.forename: Hiral
authors.initials: H
authors.lastname: Patel
authors.affiliation: 3 Computational Biology, Biogen, Inc., Cambridge, Massachusetts.
authors.forename: Norm
authors.initials: N
authors.lastname: Allaire
authors.affiliation: 3 Computational Biology, Biogen, Inc., Cambridge, Massachusetts.
authors.forename: Alice
authors.initials: A
authors.lastname: Thai
authors.affiliation: 3 Computational Biology, Biogen, Inc., Cambridge, Massachusetts.
authors.forename: Patrick
authors.initials: P
authors.lastname: Cullen
authors.affiliation: 4 Immunology Research, Biogen, Inc., Cambridge, Massachusetts.
authors.forename: Sarah
authors.initials: S
authors.lastname: Ryan
authors.affiliation: 4 Immunology Research, Biogen, Inc., Cambridge, Massachusetts.
authors.forename: Matvey
authors.initials: M
authors.lastname: Lukashev
authors.affiliation: 4 Immunology Research, Biogen, Inc., Cambridge, Massachusetts.
authors.forename: Pradeep
authors.initials: P
authors.lastname: Bista
authors.affiliation: 5 DMPK, Biogen, Inc., Cambridge, Massachusetts.
authors.forename: Ron
authors.initials: R
authors.lastname: Huang
authors.affiliation: 1 Neurology Research, Biogen, Inc., Cambridge, Massachusetts.
authors.forename: Kenneth J
authors.initials: KJ
authors.lastname: Rhodes
authors.affiliation: 1 Neurology Research, Biogen, Inc., Cambridge, Massachusetts.
authors.forename: Robert H
authors.initials: RH
authors.lastname: Scannevin
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D000069462:Dimethyl Fumarate / Q000008:administration & dosage / Q000493:pharmacokinetics*; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D005786:Gene Expression Regulation / Q000187:drug effects; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D009928:Organ Specificity; D014018:Tissue Distribution; D059467:Transcriptome / Q000187:drug effects
chemical_list: D000893:Anti-Inflammatory Agents; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D000069462:Dimethyl Fumarate