Background: Dimethyl fumarate (DMF) has immune-modulatory and neuro-protective characteristics that can be used for treatment of acute ischemic stroke.
Objective: To investigate the therapeutic effects of DMF on histological and functional recovery of rats after transient middle cerebral artery (MCA) occlusion.
Methods: 22 Sprague-Dawley male rats weighing 275–300 g were randomized into three groups by block randomization. In the sham group (n = 7), the neck was opened, but neither MCA was occluded, nor any drug was administered.
The control group (n = 7) was treated with vehicle (methocel) by gavage for 14 days after MCA occlusion. In the DMF-treated group (n = 8), treatment was performed with 15 mg/kg body weight dimethyl fumarate twice a day for 14 days after MCA occlusion. Transient occlusion of the right MCA was performed by intraluminal thread method in the DMF-treated and the control group. Neurological deficit score (NDS), pole test, and adhesive removal test were performed before the surgery, and on post-operative Days 0, 3, 5, 7, 10, and 14. After the final behaviour test, the animals’ brains were perfused and removed. Brains were frozen and sectioned serially and coronally using a cryostat. Infract volume and brain volume were estimated by stereology.
Results: The percentage of infarct volume was significantly lower in DMF-treated animals (5.76%) than in the control group (22.39%) (P < 0.0001). Regarding behavioural tests, the DMF-treated group showed better function in NDS on Days 7 (P = 0.041) and 10 (P = 0.046), but not in pole and adhesive removal tests. There was no significant correlation between behavioural tests and histological results.
Conclusion: Dimethyl fumarate could be beneficial as a potential neuroprotective agent in the treatment of stroke.
AnsariS., AzariH., McConnellD.J., AfzalA., & MoccoJ. (2011) Intraluminal middle cerebral artery occlusion (MCAO) model for ischemic stroke with laser doppler flowmetry guidance in mice. Journal of Visualized Experiments, (51), 2879. doi: 10.3791/2879
2.
BalkayaM., KroberJ., GertzK., PeruzzaroS., & EndresM. (2013) Characterization of long-term functional outcome in a murine model of mild brain ischemia. Journal of Neuroscience Methods, 213(2), 179–187. doi: 10.1016/j.jneumeth.2012.12.021
Borhani-HaghighiA., SafariR., HeydariS.T., SoleimaniF., SharifianM., Yektaparast KashkuliS., ..., & Cruz-FloresS. (2013) Hospital Mortality Associated with Stroke in Southern Iran. Iranian Journal of Medical Sciences, 38(4), 314–320.
5.
DeVriesA.C., NelsonR.J., TraystmanR.J., & HurnP.D. (2001) Cognitive and behavioral assessment in experimental stroke research: Will it prove useful?Neuroscience & Biobehoural Reviews, 25(4), 325–342.
6.
EllrichmannG., Petrasch-ParwezE., LeeD.H., ReickC., ArningL., SaftC., ..., & LinkerR. A. (2011) Efficacy of fumaric acid esters in the R6/2 and YAC128 models of huntington’s disease. PLoS One, 6(1), e16172. doi: 10.1371/journal.pone.0016172
7.
EmmanouilD.E., & QuockR.M. (2007) Advances in understanding the actions of nitrous oxide. Anesthesia Progress, 54(1), 9–18. doi: 10.2344/0003-3006(2007)54[9:AIUTAO]2.0.CO;2
8.
FoxR.J., MillerD.H., PhillipsJ.T., HutchinsonM., HavrdovaE., KitaM., ..., & DawsonK.T. (2012) Placebo-controlled phase 3 study of oral BG-12 or glatiramer in multiple sclerosis. The New England Journal of Medicine, 367(12), 1087–1097. doi: 10.1056/NEJMoa1206328
9.
FreretT., BouetV., LeconteC., RousselS., ChazalvielL., DivouxD., ..., & BoulouardM. (2009) Behavioral deficits after distal focal cerebral ischemia in mice: Usefulness of adhesive removal test. Behoral Neuroscience, 123(1), 224–230. doi: 10.1037/a0014157
10.
GoldR., KapposL., ArnoldD.L., Bar-OrA., GiovannoniG., SelmajK., ..., & DawsonK.T. (2012) Placebo-controlled phase 3 study of oral BG-12 for relapsing multiple sclerosis. New England Journal of Medicine, 367(12), 1098–1107. doi: 10.1056/NEJMoa1114287
11.
GoldsteinL.B. (1995) Right vs. left sensorimotor cortex suction-ablation in the rat: No difference in beam-walking recovery. Brain Research, 674(1), 167–170.
12.
JefferyD.R. (2013) Recent advances in treating multiple sclerosis: Efficacy, risks and place in therapy. Therapeutic Advances in Chronic Disease, 4(1), 45–51. doi: 10.1177/2040622312466279
13.
KelsenJ., LarsenM.H., SørensenJ.C., MøllerA., FrøkiærJ., NielsenS., ..., & RønnL.C.B. (2010) Neuronal precursor cell proliferation in the hippocampus after transient cerebral ischemia: A comparative study of two rat strains using stereological tools. Experimental and Translational Stroke Medicine, 2, 8–8. doi: 10.1186/2040-7378-2-8
14.
KimS.J., KimB.K., KoY.J., BangM.S., KimM.H., & HanT.R. (2010) Functional and histologic changes after repeated transcranial direct current stimulation in rat stroke model. Journal of Korean Medical Science, 25(10), 1499–1505. doi: 10.3346/jkms.2010.25.10.1499
15.
KunzeA., ZierathD., DrogomiretskiyO., & BeckerK. (2014) Variation in behavioral deficits and patterns of recovery after stroke among different rat strains. Translational Stroke Research, 5(5), 569–576. doi: 10.1007/s12975-014-0337-y
16.
LinR., CaiJ., KostukE.W., RosenwasserR., & IacovittiL. (2016) Fumarate modulates the immune/inflammatory response and rescues nerve cells and neurological function after stroke in rats. Journal of Neuroinflammation, 13(1), 269.
17.
LinkerR.A., LeeD.H., RyanS., van DamA.M., ConradR., BistaP., ..., & GoldR. (2011) Fumaric acid esters exert neuroprotective effects in neuroinflammation via activation of the Nrf2 antioxidant pathway. Brain, 134(Pt 3), 678–692. doi: 10.1093/brain/awq386
18.
LipsanenA., & JolkkonenJ. (2011) Experimental approaches to study functional recovery following cerebral ischemia. Cellular and Molecular Life Science, 68(18), 3007–3017. doi: 10.1007/s00018-011-0733-3
19.
LiuF., & McCulloughL.D. (2011) Middle cerebral artery occlusion model in rodents: Methods and potential pitfalls. Journal of Biomedicine and Biotechnology, 2011, 464701. doi: 10.1155/2011/464701
20.
LongaE.Z., WeinsteinP.R., CarlsonS., & CumminsR. (1989) Reversible middle cerebral artery occlusion without craniectomy in rats. Stroke, 20(1), 84–91.
21.
Moharregh-KhiabaniD., BlankA., SkripuletzT., MillerE., KotsiariA., GudiV., & StangelM. (2010) Effects of fumaric acids on cuprizone induced central nervous system De- and remyelination in the mouse. PLoS One, 5(7), e11769. doi: 10.1371/journal.pone.0011769
22.
Moharregh-KhiabaniD., LinkerR.A., GoldR., & StangelM. (2009) Fumaric acid and its esters: An emerging treatment for multiple sclerosis. Current Neuropharmacology, 7(1), 60–64. doi: 10.2174/157015909787602788
23.
MrowietzU., & AsadullahK. (2005) Dimethylfumarate for psoriasis: More than a dietary curiosity. Trends in Molecular Medicine, 11(1), 43–48. doi: 10.1016/j.molmed.2004.11.003
PillaiD.R., DittmarM.S., BaldaranovD., HeidemannR.M., HenningE.C., SchuiererG., ..., & SchlachetzkiF. (2009) Cerebral ischemia-reperfusion injury in rats–a 3 T MRI study on biphasic blood-brain barrier opening and the dynamics of edema formation. Journal of Cerebral Blood Flow and Metabolism, 29(11), 1846–1855. doi: 10.1038/jcbfm.2009.106
26.
ShahtaheriR.A., Borhani HaghighiA., SafariA., & Cruz-FloresS. (2012) Recombinant tissue plasminogen activator (rtPA) and stroke unit for acute ischaemic stroke in developing countries, are they cost-effective? E. International Journal of Stroke, 7(7), 9. doi: 10.1111/j.1747-4949.2012.00892.x
27.
VeselkinaO.S., MorozovV.A., KorzhevskiiD.E., TihonovD.B., BaryginO.I., IsaevaA.V., ..., & VlasovT.D. (2015) Neuroprotective activity of creatylglycine ethyl ester fumarate. Journal of Stroke and Cerebrovascular Diseases, 24(3), 591–600. doi: 10.1016/j.jstrokecerebrovasdis.2014.10.005
28.
WanL., ChengY., LuoZ., GuoH., ZhaoW., GuQ., ..., & GuoJ. (2015) Neuroprotection, learning and memory improvement of a standardized extract from Renshen Shouwu against neuronal injury and vascular dementia in rats with brain ischemia. Journal of Ethnopharmacology, 165, 118–126. doi: 10.1016/j.je2015.02.027
29.
WangQ., TangX.N., & YenariM.A. (2007) The inflammatory response in stroke. Journal of Neuroimmunology, 184(1-2), 53–68. doi: 10.1016/j.jneuroim.2006.11.014
30.
WilmsH., SieversJ., RickertU., Rostami-YazdiM., MrowietzU., & LuciusR. (2010) Dimethylfumarate inhibits microglial and astrocytic inflammation by suppressing the synthesis of nitric oxide, IL-beta, TNF-alpha and IL-6 in an in-vitro model of brain inflammation. Journal of Neuroinflammation, 7, 30. doi: 10.1186/1742-2094-7-30
31.
YangJ.L., SykoraP., WilsonD.M.3rd, MattsonM.P., & BohrV.A. (2011) The excitatory neurotransmitter glutamate stimulates DNA repair to increase neuronal resiliency. Mechanisms of Ageing and Development, 132(8-9), 405–411. doi: 10.1016/j.mad.2011.06.005
