Abstract
Background 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 24. h 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.
Original language | English |
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Pages (from-to) | 349-358 |
Number of pages | 10 |
Journal | Neurobiology of Disease |
Volume | 82 |
DOIs | |
State | Published - Oct 1 2015 |
ASJC Scopus Subject Areas
- Neurology
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)
- Intercellular Adhesion Molecule-1/metabolism
- Male
- Brain Edema/drug therapy
- Dimethyl Fumarate/pharmacology
- MafG Transcription Factor/genetics
- NF-E2-Related Factor 2/metabolism
- Disease Models, Animal
- Microglia/drug effects
- Casein Kinase II/antagonists & inhibitors
- Acrylates/pharmacology
- Neuroprotective Agents/pharmacology
- Repressor Proteins/genetics
- Collagenases
- Animals
- Blood-Brain Barrier/drug effects
- Neuroimmunomodulation/drug effects
- Cerebral Hemorrhage/drug therapy
- Mice
- Protein Kinase Inhibitors/pharmacology
- Phosphorylation/drug effects