title: Dimethyl Fumarate Protects Brain From Damage Produced by Intracerebral Hemorrhage by Mechanism Involving Nrf2.
abstract: OBJECTIVE
  Intracerebral hemorrhage (ICH) represents a devastating form of stroke for which there is no effective treatment. This preclinical study was designed to evaluate dimethyl fumarate (DMF), a substance recently approved for the treatment of multiple sclerosis, as therapy for ICH. We hypothesized that DMF through activating the master regulator of cellular self-defense responses, transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2), would act as effective treatment for ICH-mediated damage.
  
  
  METHODS
  Male rats and mice, including Nrf2 knockouts, were subjected to intracerebral injection of blood (to mimic ICH) and then treated with DMF. Neurological deficit, brain edema, gene induction profile and hematoma resolution were evaluated. Phagocytic functions of primary microglia in culture were used to study hematoma resolution.
  
  
  RESULTS
  Treatment with DMF induced Nrf2-target genes, improved hematoma resolution, reduced brain edema, and ultimately enhanced neurological recovery in rats and wild-type, but not Nrf2 knockout, mice. Most importantly, the treatment of ICH with DMF showed a 24 h window of therapeutic opportunity.
  
  
  CONCLUSIONS
  A clinically relevant dose of DMF demonstrates potent therapeutic efficacy and impressive 24 h therapeutic window of opportunity. This study merits further evaluation of this compound as potential treatment for ICH in humans.
authors.affiliation: From the Stroke Program-Department of Neurology, University of Texas-Houston, Medical School.
authors.forename: Xiurong
authors.initials: X
authors.lastname: Zhao
authors.affiliation: From the Stroke Program-Department of Neurology, University of Texas-Houston, Medical School.
authors.forename: Guanghua
authors.initials: G
authors.lastname: Sun
authors.affiliation: From the Stroke Program-Department of Neurology, University of Texas-Houston, Medical School.
authors.forename: Jie
authors.initials: J
authors.lastname: Zhang
authors.affiliation: From the Stroke Program-Department of Neurology, University of Texas-Houston, Medical School.
authors.forename: Shun-Ming
authors.initials: SM
authors.lastname: Ting
authors.affiliation: From the Stroke Program-Department of Neurology, University of Texas-Houston, Medical School.
authors.forename: Nicole
authors.initials: N
authors.lastname: Gonzales
authors.affiliation: From the Stroke Program-Department of Neurology, University of Texas-Houston, Medical School. j.aronowski@uth.tmc.edu.
authors.forename: Jaroslaw
authors.initials: J
authors.lastname: Aronowski
mesh_terms: D000818:Animals; D002543:Cerebral Hemorrhage / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control*; D000069462:Dimethyl Fumarate; D005650:Fumarates / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D051267:NF-E2-Related Factor 2 / Q000819:agonists / Q000096:biosynthesis* / Q000172:deficiency; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D005650:Fumarates; D051267:NF-E2-Related Factor 2; D018696:Neuroprotective Agents; C495636:Nfe2l2 protein, mouse; D000069462:Dimethyl Fumarate
keywords: dimethyl fumarate; hematoma; inflammation; intracerebral hemorrhage; microglia; phagocytosis