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Fumarate decreases edema volume and improves functional outcome after experimental stroke

Clausen, Bettina Hjelm; Lundberg, Louise; Yli-Karjanmaa, Minna; Martin, Nellie Anne; Svensson, Martina LU ; Alfsen, Maria Zeiler; Flæng, Simon Bertram; Lyngsø, Kristina; Boza-Serrano, Antonio LU and Nielsen, Helle H, et al. (2017) In Experimental Neurology 295. p.144-154
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, 20 mg/kg MMF was administered intravenously. Outcomes were evaluated 6, 24 and 48 h after pMCAO. First, we examined whether a bolus of MMF was capable of changing expression of kelch-like erythroid cell-derived protein with CNC... (More)

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, 20 mg/kg MMF was administered intravenously. Outcomes were evaluated 6, 24 and 48 h 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 48 h after pMCAO using multiplex electrochemoluminiscence analysis. Results Administration of MMF increased the protein level of Nrf2 6 h after pMCAO, and improved functional outcome at 24 and 48 h after pMCAO. MMF treatment did not influence infarct size, however reduced edema volume at both 24 and 48 h after pMCAO. MMF treatment resulted in increased Hsp72 expression in the brain 6 h after pMCAO. Hcar2 mRNA levels increased significantly 24 h 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 6 h after pMCAO, and additionally reduced the level of the pro-inflammatory cytokine IL-12p70 in the brain at 24 and 48 h 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.

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keywords
Cytokines, Dimethyl-fumarate, Focal cerebral ischemia, Heat shock protein, Monomethyl-fumarate, Nrf2, Tecfidera
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Experimental Neurology
volume
295
pages
11 pages
publisher
Academic Press
external identifiers
  • scopus:85020449767
  • wos:000406820900014
ISSN
0014-4886
DOI
10.1016/j.expneurol.2017.06.011
language
English
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yes
id
529e5e33-91a3-4272-8c5f-3ffa9a116768
date added to LUP
2017-06-26 11:48:23
date last changed
2018-02-11 04:29:44
@article{529e5e33-91a3-4272-8c5f-3ffa9a116768,
  abstract     = {<p>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, 20 mg/kg MMF was administered intravenously. Outcomes were evaluated 6, 24 and 48 h 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 48 h after pMCAO using multiplex electrochemoluminiscence analysis. Results Administration of MMF increased the protein level of Nrf2 6 h after pMCAO, and improved functional outcome at 24 and 48 h after pMCAO. MMF treatment did not influence infarct size, however reduced edema volume at both 24 and 48 h after pMCAO. MMF treatment resulted in increased Hsp72 expression in the brain 6 h after pMCAO. Hcar2 mRNA levels increased significantly 24 h 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 6 h after pMCAO, and additionally reduced the level of the pro-inflammatory cytokine IL-12p70 in the brain at 24 and 48 h 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.</p>},
  author       = {Clausen, Bettina Hjelm and Lundberg, Louise and Yli-Karjanmaa, Minna and Martin, Nellie Anne and Svensson, Martina and Alfsen, Maria Zeiler and Flæng, Simon Bertram and Lyngsø, Kristina and Boza-Serrano, Antonio and Nielsen, Helle H and Hansen, Pernille B. and Finsen, Bente and Deierborg, Tomas and Illes, Zsolt and Lambertsen, Kate Lykke},
  issn         = {0014-4886},
  keyword      = {Cytokines,Dimethyl-fumarate,Focal cerebral ischemia,Heat shock protein,Monomethyl-fumarate,Nrf2,Tecfidera},
  language     = {eng},
  month        = {09},
  pages        = {144--154},
  publisher    = {Academic Press},
  series       = {Experimental Neurology},
  title        = {Fumarate decreases edema volume and improves functional outcome after experimental stroke},
  url          = {http://dx.doi.org/10.1016/j.expneurol.2017.06.011},
  volume       = {295},
  year         = {2017},
}