title: Fumarate modulates the immune/inflammatory response and rescues nerve cells and neurological function after stroke in rats.
abstract: Dimethyl fumarate (DMF), working via its metabolite monomethylfumarate (MMF), acts as a potent antioxidant and immunomodulator in animal models of neurologic disease and in patients with multiple sclerosis. These properties and their translational potential led us to investigate whether DMF/MMF could also protect at-risk and/or dying neurons in models of ischemic stroke in vitro and in vivo. Although the antioxidant effects have been partially addressed, the benefits of DMF immunomodulation after ischemic stroke still need to be explored.
  
  
  
  In vitro neuronal culture with oxygen-glucose deprivation and rats with middle cerebral artery occlusion were subjected to DMF/MMF treatment. Live/dead cell counting and LDH assay, as well as behavioral deficits, plasma cytokine assay, western blots, real-time PCR (Q-PCR) and immunofluorescence staining, were used to evaluate the mechanisms and neurological outcomes.
  
  
  
  We found that MMF significantly rescued cortical neurons from oxygen-glucose deprivation (OGD) in culture and suppressed pro-inflammatory cytokines produced by primary mixed neuron/glia cultures subjected to OGD. In rats, DMF treatment significantly decreased infarction volume by nearly 40 % and significantly improved neurobehavioral deficits after middle cerebral artery occlusion (MCAO). In the acute early phase (72 h after MCAO), DMF induced the expression of transcription factor Nrf2 and its downstream mediator HO-1, important for the protection of infarcted cells against oxidative stress. In addition to its antioxidant role, DMF also acted as a potent immunomodulator, reducing the infiltration of neutrophils and T cells and the number of activated microglia/macrophages in the infarct region by more than 50 % by 7-14 days after MCAO. Concomitantly, the levels of potentially harmful pro-inflammatory cytokines were greatly reduced in the plasma and brain and in OGD neuron/glia cultures.
  
  
  
  We conclude that DMF is neuroprotective in experimental stroke because of its potent immunomodulatory and antioxidant effects and thus may be useful as a novel therapeutic agent to treat stroke in patients.
authors.affiliation: The Joseph and Marie Field Cerebrovascular Research Laboratory at Jefferson, Vickie & Jack Farber Institute for Neurosciences, Department of Neuroscience, Sidney Kimmel Medical College, Thomas Jefferson University, 900 Walnut Street, Philadelphia, PA, 19107, USA.
authors.forename: Ruihe
authors.initials: R
authors.lastname: Lin
authors.affiliation: The Joseph and Marie Field Cerebrovascular Research Laboratory at Jefferson, Vickie & Jack Farber Institute for Neurosciences, Department of Neuroscience, Sidney Kimmel Medical College, Thomas Jefferson University, 900 Walnut Street, Philadelphia, PA, 19107, USA.
authors.forename: Jingli
authors.initials: J
authors.lastname: Cai
authors.affiliation: The Joseph and Marie Field Cerebrovascular Research Laboratory at Jefferson, Vickie & Jack Farber Institute for Neurosciences, Department of Neuroscience, Sidney Kimmel Medical College, Thomas Jefferson University, 900 Walnut Street, Philadelphia, PA, 19107, USA.
authors.forename: Eric W
authors.initials: EW
authors.lastname: Kostuk
authors.affiliation: The Joseph and Marie Field Cerebrovascular Research Laboratory at Jefferson, Vickie & Jack Farber Institute for Neuroscience, Department of Neurological Surgery, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA, 19107, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Rosenwasser
authors.affiliation: The Joseph and Marie Field Cerebrovascular Research Laboratory at Jefferson, Vickie & Jack Farber Institute for Neurosciences, Department of Neuroscience, Sidney Kimmel Medical College, Thomas Jefferson University, 900 Walnut Street, Philadelphia, PA, 19107, USA. Lorraine.iacovitti@jefferson.edu.
authors.forename: Lorraine
authors.identifier: 0000-0002-2996-2460
authors.initials: L
authors.lastname: Iacovitti
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D000069462:Dimethyl Fumarate / Q000494:pharmacology / Q000627:therapeutic use*; D007111:Immunity, Cellular / Q000187:drug effects* / Q000502:physiology; D018836:Inflammation Mediators / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000378:metabolism; D008297:Male; D009474:Neurons / Q000187:drug effects* / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D020127:Recovery of Function / Q000187:drug effects* / Q000502:physiology; D020521:Stroke / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism
chemical_list: D018836:Inflammation Mediators; D000069462:Dimethyl Fumarate
keywords: Dimethyl fumarate; Inflammation; Stroke