Therapeutic effects of oral dimethyl fumarate on stroke induced by middle cerebral artery occlusion: An animal experimental study

Article type: Research Article

Authors: Safari, Anahid^{a; b} | Fazeli, Mehdi^{b; *} | Namavar, Mohammad Reza^{c; d; e} | Tanideh, Nader^{f; g} | Jafari, Peyman^h | Borhani-Haghighi, Afshin^{c; i}

Affiliations: [a] Endocrinology and Metabolism Research Center, Shiraz University of Medical Sciences, Shiraz, Iran | [b] Department of Pharmacology, Shiraz University, Shiraz, Iran | [c] Clinical Neurology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran | [d] Histomorphometry and stereology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran | [e] Departmentof Anatomy, Shiraz University of Medical Sciences, Shiraz, Iran | [f] Stem Cells Technology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran | [g] Department of Pharmacology, Shiraz University of Medical Sciences, Shiraz, Iran | [h] Department of Biostatistics, Shiraz University of Medical Sciences, Shiraz, Iran | [i] Department of Neurology, Shiraz University of Medical Sciences, Shiraz, Iran

Correspondence: [*] Corresponding author: Mehdi Fazeli, PhD, Department of Pharmacology, Shiraz University, Shiraz University Campus,Shiraz, Iran. Tel./Fax: +98 713 627 2287; E-mail: [email protected].

Abstract: 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.

Keywords: Stroke, Cerebrovascular accident, dimethyl fumarate, middle cerebral artery occlusion, neuroprotection

DOI: 10.3233/RNN-160670

Journal: Restorative Neurology and Neuroscience, vol. 35, no. 3, pp. 265-274, 2017