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Dimethyl fumarate confers neuroprotection by casein kinase 2 phosphorylation of Nrf2 in murine intracerebral hemorrhage.

AbstractBACKGROUND AND PURPOSE:
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.
CONCLUSION:
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.
AuthorsLoretta O Iniaghe, Paul R Krafft, Damon W Klebe, Eric K I Omogbai, John H Zhang, Jiping Tang
JournalNeurobiology of disease (Neurobiol Dis) Vol. 82 Pg. 349-358 (Oct 2015) ISSN: 1095-953X [Electronic] United States
PMID26176793 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
CopyrightCopyright © 2015 Elsevier Inc. All rights reserved.
Chemical References
  • (E)-3-(2,3,4,5-tetrabromophenyl)acrylic acid
  • Acrylates
  • Icam1 protein, mouse
  • MafG Transcription Factor
  • Mafg protein, mouse
  • NF-E2-Related Factor 2
  • Neuroprotective Agents
  • Nfe2l2 protein, mouse
  • Protein Kinase Inhibitors
  • Repressor Proteins
  • Intercellular Adhesion Molecule-1
  • Casein Kinase II
  • Collagenases
  • Dimethyl Fumarate
Topics
  • Acrylates (pharmacology)
  • Animals
  • Blood-Brain Barrier (drug effects, enzymology)
  • Brain Edema (drug therapy, enzymology)
  • Casein Kinase II (antagonists & inhibitors, metabolism)
  • Cerebral Hemorrhage (drug therapy, enzymology)
  • Collagenases
  • Dimethyl Fumarate (pharmacology)
  • Disease Models, Animal
  • Intercellular Adhesion Molecule-1 (metabolism)
  • MafG Transcription Factor (genetics, metabolism)
  • Male
  • Mice
  • Microglia (drug effects, enzymology)
  • NF-E2-Related Factor 2 (metabolism)
  • Neuroimmunomodulation (drug effects, physiology)
  • Neuroprotective Agents (pharmacology)
  • Phosphorylation (drug effects)
  • Protein Kinase Inhibitors (pharmacology)
  • Repressor Proteins (genetics, metabolism)

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