title: Dimethyl fumarate confers neuroprotection by casein kinase 2 phosphorylation of Nrf2 in murine intracerebral hemorrhage.
abstract: OBJECTIVE
  Edema formation, inflammation and increased blood-brain barrier permeability contribute to poor outcomes after intracerebral hemorrhage (ICH). This study examined the therapeutic effect of dimethyl fumarate (DMF), a fumaric acid ester that activates nuclear factor erythroid-2 related factor 2 (Nrf2) and Nrf2 heterodimerization effector protein musculo-aponeurotic fibrosarcoma-G (MAFG) in a murine ICH model.
  
  
  METHODS
  Male CD-1 mice (n=176) were subjected to intrastriatal infusion of bacterial collagenase (n=126), autologous blood (n=18) or sham surgery (n=32). Four (4) animals not subjected to ICH (naive) were also included in the study. After ICH, animals either received vehicle, dimethyl fumarate (10 mg or 100 mg/kg) or casein kinase 2 inhibitor (E)-3-(2,3,4,5-tetrabromophenyl)acrylic acid (TBCA). Thirty-two mice also received scrambled siRNA or MAFG siRNA 24h before ICH. Brain water content and neurological function were evaluated.
  
  
  RESULTS
  Dimethyl fumarate reduced Evans blue dye extravasation, decreased brain water content, and improved neurological deficits at 24 and 72 h after ICH. Casein kinase 2 inhibitor TBCA and MAFG siRNA prevented the effect of dimethyl fumarate on brain edema and neurological function. After ICH, ICAM-1 levels increased and casein kinase 2 levels decreased. Dimethyl fumarate reduced ICAM-1 but enhanced casein kinase 2 levels. Again, casein kinase 2 inhibitor TBCA and MAFG siRNA abolished the effect of dimethyl fumarate on ICAM-1 and casein kinase 2. Dimethyl fumarate preserved pNrf2 and MAFG expression in the nuclear lysate after ICH and the effect of dimethyl fumarate was abolished by casein kinase 2 inhibitor TBCA and MAFG siRNA. Dimethyl fumarate reduced microglia activation in peri-hematoma areas after ICH. The protective effect of dimethyl fumarate on brain edema and neurological function was also observed in a blood injection mouse model.
  
  
  CONCLUSIONS
  Dimethyl fumarate ameliorated inflammation, reduced blood-brain barrier permeability, and improved neurological outcomes by casein kinase 2 and Nrf2 signaling pathways after experimental ICH in mice.
authors.affiliation: Department of Physiology and Pharmacology, Loma Linda University, USA; Department of Pharmacology and Toxicology, University of Benin, Nigeria.
authors.forename: Loretta O
authors.initials: LO
authors.lastname: Iniaghe
authors.affiliation: Department of Physiology and Pharmacology, Loma Linda University, USA; Department of Neurosurgery, Loma Linda University, Loma Linda, CA, USA.
authors.forename: Paul R
authors.initials: PR
authors.lastname: Krafft
authors.affiliation: Department of Physiology and Pharmacology, Loma Linda University, USA.
authors.forename: Damon W
authors.initials: DW
authors.lastname: Klebe
authors.affiliation: Department of Pharmacology and Toxicology, University of Benin, Nigeria.
authors.forename: Eric K I
authors.initials: EKI
authors.lastname: Omogbai
authors.affiliation: Department of Physiology and Pharmacology, Loma Linda University, USA; Department of Anesthesiology, Loma Linda University, Loma Linda, CA, USA.
authors.forename: John H
authors.initials: JH
authors.lastname: Zhang
authors.affiliation: Department of Physiology and Pharmacology, Loma Linda University, USA. Electronic address: jtang@llu.edu.
authors.forename: Jiping
authors.initials: J
authors.lastname: Tang
mesh_terms: D000179:Acrylates / Q000494:pharmacology; D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000201:enzymology; D001929:Brain Edema / Q000188:drug therapy / Q000201:enzymology; D047390:Casein Kinase II / Q000037:antagonists & inhibitors / Q000378:metabolism*; D002543:Cerebral Hemorrhage / Q000188:drug therapy* / Q000201:enzymology; D017364:Collagenases; D000069462:Dimethyl Fumarate / Q000494:pharmacology*; D004195:Disease Models, Animal; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D051259:MafG Transcription Factor / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D017628:Microglia / Q000187:drug effects / Q000201:enzymology; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D015213:Neuroimmunomodulation / Q000187:drug effects / Q000502:physiology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: C000590659:(E)-3-(2,3,4,5-tetrabromophenyl)acrylic acid; D000179:Acrylates; C090509:Icam1 protein, mouse; D051259:MafG Transcription Factor; C491247:Mafg protein, mouse; D051267:NF-E2-Related Factor 2; D018696:Neuroprotective Agents; C495636:Nfe2l2 protein, mouse; D047428:Protein Kinase Inhibitors; D012097:Repressor Proteins; D018799:Intercellular Adhesion Molecule-1; D047390:Casein Kinase II; D017364:Collagenases; D000069462:Dimethyl Fumarate
keywords: Casein kinase 2; Dimethyl fumarate; Evans Blue extravasation; Inflammation; Intracerebral hemorrhage; Musculo-aponeurotic fibrosarcoma-G; Phosphorylated nuclear factor erythroid-2 related factor 2 (Nrf2)