title: Dimethyl fumarate alters microglia phenotype and protects neurons against proinflammatory toxic microenvironments.
abstract: Delayed-release dimethyl fumarate (DMF) is an approved treatment for multiple sclerosis (MS). Microglia are considered central to MS pathophysiology, however the effects of DMF and the primary metabolite monomethyl fumarate (MMF) on microglia are not well characterized. We demonstrated that DMF and MMF altered transcriptional responses in primary microglia related to the nuclear factor (erythroid-derived 2)-like 2 pathway. Additionally, through an NRF2 independent manner, DMF, but not MMF significantly reduced production of proinflammatory mediators in classically activated microglia, and further rescued mitochondrial respiratory deficits in primary cortical neurons that were induced by activated microglia. These data suggest the mechanism of action of DMF may involve modulation of microglia inflammatory responses and attenuation of neurotoxicity.
authors.affiliation: Biogen, Inc., 225 Binney St, Cambridge, MA 02142, United States. Electronic address: Haiyan_Peng@Eisai.com.
authors.forename: Haiyan
authors.initials: H
authors.lastname: Peng
authors.affiliation: Biogen, Inc., 225 Binney St, Cambridge, MA 02142, United States.
authors.forename: Huo
authors.initials: H
authors.lastname: Li
authors.affiliation: Biogen, Inc., 225 Binney St, Cambridge, MA 02142, United States.
authors.forename: Adam
authors.initials: A
authors.lastname: Sheehy
authors.affiliation: Biogen, Inc., 225 Binney St, Cambridge, MA 02142, United States.
authors.forename: Patrick
authors.initials: P
authors.lastname: Cullen
authors.affiliation: Biogen, Inc., 225 Binney St, Cambridge, MA 02142, United States.
authors.forename: Norm
authors.initials: N
authors.lastname: Allaire
authors.affiliation: Biogen, Inc., 225 Binney St, Cambridge, MA 02142, United States.
authors.forename: Robert H
authors.initials: RH
authors.lastname: Scannevin
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D060833:Cellular Microenvironment / Q000187:drug effects* / Q000502:physiology; D000069462:Dimethyl Fumarate / Q000494:pharmacology*; D005650:Fumarates / Q000494:pharmacology; D007166:Immunosuppressive Agents / Q000494:pharmacology; D018836:Inflammation Mediators / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008297:Male; D008298:Maleates / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000187:drug effects* / Q000378:metabolism; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology*; D010641:Phenotype; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D005650:Fumarates; D007166:Immunosuppressive Agents; D018836:Inflammation Mediators; D008298:Maleates; D018696:Neuroprotective Agents; C073341:citraconic acid; D000069462:Dimethyl Fumarate
keywords: Cytokine; Dimethyl fumarate; LPS+IFN-γ; Microglia; Mitochondrial respiration; Monomethyl fumarate