Bettina Hjelm Clausen1, Louise Lundberg2, Minna Yli-Karjanmaa3, Nellie Anne Martin4, Martina Svensson5, Maria Zeiler Alfsen6, Simon Bertram Flæng7, Kristina Lyngsø8, Antonio Boza-Serrano9, Helle H Nielsen10, Pernille B Hansen11, Bente Finsen12, Tomas Deierborg13, Zsolt Illes14, Kate Lykke Lambertsen15. 1. Department of Neurobiology Research, Institute of Molecular Medicine, University of Southern Denmark, J.B. Winsloewsvej 21-25, DK-5000 Odense C, Denmark. Electronic address: bclausen@health.sdu.dk. 2. Department of Neurobiology Research, Institute of Molecular Medicine, University of Southern Denmark, J.B. Winsloewsvej 21-25, DK-5000 Odense C, Denmark. 3. Department of Neurobiology Research, Institute of Molecular Medicine, University of Southern Denmark, J.B. Winsloewsvej 21-25, DK-5000 Odense C, Denmark. Electronic address: myli@health.sdu.dk. 4. Department of Neurobiology Research, Institute of Molecular Medicine, University of Southern Denmark, J.B. Winsloewsvej 21-25, DK-5000 Odense C, Denmark; Department of Neurology, Odense University Hospital, J.B. Winsloewsvej 4, DK-5000 Odense C, Denmark. Electronic address: nmartin@health.sdu.dk. 5. Department of Experimental Medical Sciences, Experimental Neuroinflammation Laboratory, Sölveg 19, Lund University, 22100 Lund, Sweden. Electronic address: martina.svensson@med.lu.se. 6. Department of Neurobiology Research, Institute of Molecular Medicine, University of Southern Denmark, J.B. Winsloewsvej 21-25, DK-5000 Odense C, Denmark. Electronic address: maalf12@student.sdu.dk. 7. Department of Neurobiology Research, Institute of Molecular Medicine, University of Southern Denmark, J.B. Winsloewsvej 21-25, DK-5000 Odense C, Denmark. Electronic address: sflaeng@health.sdu.dk. 8. Department of Cardiovascular and Renal Research, Institute of Molecular Medicine, University of Southern Denmark, J.B. Winsloewsvej 21 3rd, DK-5000 Odense C, Denmark. Electronic address: klyngso@health.sdu.dk. 9. Department of Experimental Medical Sciences, Experimental Neuroinflammation Laboratory, Sölveg 19, Lund University, 22100 Lund, Sweden. Electronic address: antonio.boza_serrano@med.lu.se. 10. Department of Neurology, Odense University Hospital, J.B. Winsloewsvej 4, DK-5000 Odense C, Denmark. Electronic address: Helle.Hvilsted.Nielsen@rsyd.dk. 11. Department of Cardiovascular and Renal Research, Institute of Molecular Medicine, University of Southern Denmark, J.B. Winsloewsvej 21 3rd, DK-5000 Odense C, Denmark. Electronic address: pbhansen@health.sdu.dk. 12. Department of Neurobiology Research, Institute of Molecular Medicine, University of Southern Denmark, J.B. Winsloewsvej 21-25, DK-5000 Odense C, Denmark; BRIDGE, Brain Research - Inter-Disciplinary Guided Excellence, Department of Clinical Research, University of Southern Denmark, J.B. Winsloewsvej 19, DK-5000 Odense C, Denmark. Electronic address: bfinsen@health.sdu.dk. 13. Department of Experimental Medical Sciences, Experimental Neuroinflammation Laboratory, Sölveg 19, Lund University, 22100 Lund, Sweden. Electronic address: Tomas.Deierborg@med.lu.se. 14. Department of Neurology, Odense University Hospital, J.B. Winsloewsvej 4, DK-5000 Odense C, Denmark; BRIDGE, Brain Research - Inter-Disciplinary Guided Excellence, Department of Clinical Research, University of Southern Denmark, J.B. Winsloewsvej 19, DK-5000 Odense C, Denmark. Electronic address: zsolt.illes@rsyd.dk. 15. Department of Neurobiology Research, Institute of Molecular Medicine, University of Southern Denmark, J.B. Winsloewsvej 21-25, DK-5000 Odense C, Denmark; Department of Neurology, Odense University Hospital, J.B. Winsloewsvej 4, DK-5000 Odense C, Denmark; BRIDGE, Brain Research - Inter-Disciplinary Guided Excellence, Department of Clinical Research, University of Southern Denmark, J.B. Winsloewsvej 19, DK-5000 Odense C, Denmark. Electronic address: klambertsen@health.sdu.dk.
Abstract
BACKGROUND: Oxidative stress and inflammation exacerbate tissue damage in the brain after ischemic stroke. Dimethyl-fumarate (DMF) and its metabolite monomethyl-fumarate (MMF) are known to stimulate anti-oxidant pathways and modulate inflammatory responses. Considering these dual effects of fumarates, we examined the effect of MMF treatment after ischemic stroke in mice. METHODS: Permanent middle cerebral artery occlusion (pMCAO) was performed using adult, male C57BL/6 mice. Thirty minutes after pMCAO, 20mg/kg MMF was administered intravenously. Outcomes were evaluated 6, 24 and 48h after pMCAO. First, we examined whether a bolus of MMF was capable of changing expression of kelch-like erythroid cell-derived protein with CNC homology-associated protein 1 (Keap1) and nuclear factor erythroid 2-related factor (Nrf)2 in the infarcted brain. Next, we studied the effect of MMF on functional recovery. To explore mechanisms potentially influencing functional changes, we examined infarct volumes, edema formation, the expression of heat shock protein (Hsp)72, hydroxycarboxylic acid receptor 2 (Hcar2), and inducible nitric oxide synthase (iNOS) in the infarcted brain using real-time PCR and Western blotting. Concentrations of a panel of pro- and anti-inflammatory cytokines (IFNγ, IL-1β, IL-2, IL-4, IL-5, IL-6, IL-10, IL-12p70, TNF) were examined in both the infarcted brain tissue and plasma samples 6, 24 and 48h after pMCAO using multiplex electrochemoluminiscence analysis. RESULTS: Administration of MMF increased the protein level of Nrf2 6h after pMCAO, and improved functional outcome at 24 and 48h after pMCAO. MMF treatment did not influence infarct size, however reduced edema volume at both 24 and 48h after pMCAO. MMF treatment resulted in increased Hsp72 expression in the brain 6h after pMCAO. Hcar2 mRNA levels increased significantly 24h after pMCAO, but were not different between saline- and MMF-treated mice. MMF treatment also increased the level of the anti-inflammatory cytokine IL-10 in the brain and plasma 6h after pMCAO, and additionally reduced the level of the pro-inflammatory cytokine IL-12p70 in the brain at 24 and 48h after pMCAO. CONCLUSIONS: A single intravenous bolus of MMF improved sensory-motor function after ischemic stroke, reduced edema formation, and increased the levels of the neuroprotective protein Hsp72 in the brain. The early increase in IL-10 and reduction in IL-12p70 in the brain combined with changes in systemic cytokine levels may also contribute to the functional recovery after pMCAO.
BACKGROUND: Oxidative stress and inflammation exacerbate tissue damage in the brain after ischemic stroke. Dimethyl-fumarate (DMF) and its metabolite monomethyl-fumarate (MMF) are known to stimulate anti-oxidant pathways and modulate inflammatory responses. Considering these dual effects of fumarates, we examined the effect of MMF treatment after ischemic stroke in mice. METHODS: Permanent middle cerebral artery occlusion (pMCAO) was performed using adult, male C57BL/6 mice. Thirty minutes after pMCAO, 20mg/kg MMF was administered intravenously. Outcomes were evaluated 6, 24 and 48h after pMCAO. First, we examined whether a bolus of MMF was capable of changing expression of kelch-like erythroid cell-derived protein with CNC homology-associated protein 1 (Keap1) and nuclear factor erythroid 2-related factor (Nrf)2 in the infarcted brain. Next, we studied the effect of MMF on functional recovery. To explore mechanisms potentially influencing functional changes, we examined infarct volumes, edema formation, the expression of heat shock protein (Hsp)72, hydroxycarboxylic acid receptor 2 (Hcar2), and inducible nitric oxide synthase (iNOS) in the infarcted brain using real-time PCR and Western blotting. Concentrations of a panel of pro- and anti-inflammatory cytokines (IFNγ, IL-1β, IL-2, IL-4, IL-5, IL-6, IL-10, IL-12p70, TNF) were examined in both the infarcted brain tissue and plasma samples 6, 24 and 48h after pMCAO using multiplex electrochemoluminiscence analysis. RESULTS: Administration of MMF increased the protein level of Nrf2 6h after pMCAO, and improved functional outcome at 24 and 48h after pMCAO. MMF treatment did not influence infarct size, however reduced edema volume at both 24 and 48h after pMCAO. MMF treatment resulted in increased Hsp72 expression in the brain 6h after pMCAO. Hcar2 mRNA levels increased significantly 24h after pMCAO, but were not different between saline- and MMF-treated mice. MMF treatment also increased the level of the anti-inflammatory cytokine IL-10 in the brain and plasma 6h after pMCAO, and additionally reduced the level of the pro-inflammatory cytokine IL-12p70 in the brain at 24 and 48h after pMCAO. CONCLUSIONS: A single intravenous bolus of MMF improved sensory-motor function after ischemic stroke, reduced edema formation, and increased the levels of the neuroprotective protein Hsp72 in the brain. The early increase in IL-10 and reduction in IL-12p70 in the brain combined with changes in systemic cytokine levels may also contribute to the functional recovery after pMCAO.
Authors: Ayla Hoogendoorn; Thomas D Avery; Jiahe Li; Christina Bursill; Andrew Abell; Peter M Grace Journal: Trends Pharmacol Sci Date: 2021-02-19 Impact factor: 14.819
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