Neuroprotective effect of dimethyl fumarate in stroke: The role of nuclear factor erythroid 2-related factor 2

Abstract

Background: There is evidence that supports the neuroprotective effects of dimethyl fumarate (DMF) in stroke. Nuclear factor erythroid 2-related factor 2 (Nrf2) has both anti-oxidant and anti-inflammatory mechanisms. We investigated the neuroprotective effects of DMF via Nrf2 activation in the cortex, striatum, and diencephalon in a middle cerebral artery occlusion (MCAO) model of stroke. Methods: 22 Sprague-Dawley male rats were randomized into 3 groups. In DMF-treated group (n = 8), rats received 15 mg/kg oral DMF twice daily by gavage from day 0 to 14 after a 60-minute MCAO. The vehicle group (n = 7) underwent MCAO and were given methocel/H₂O, using the same method and schedule. In the sham group (n = 7), neck was opened, but neither middle cerebral artery (MCA) was occluded nor any drug was administered. After 14 days, the animals were sacrificed. The infarct volume were assessed by stereology method. Nrf2 expression was evaluated in the cortex, striatum, and diencephalon by immunohistochemistry method. Results: Ratio of infarct to total brain volume was significantly lower in the DMF-treated group (5.76%) in comparison with the vehicle group (22.39%) (P < 0.0001). Nrf2 expression was higher in DMF-treated group in comparison with both the vehicle and sham groups in cortex, striatum, diencephalon, and total brain (P < 0.0001). In the DMF-treated group, significant negative correlation between Nrf2 expression and infarct volume was observed in cortex, striatum, diencephalon, and total brain. Conclusion: DMF induces Nrf2 expression and its neuroprotective effects in different brain anatomical regions.

Keywords: Dimethyl Fumarate; Middle Cerebral Artery; Nuclear Factor Erythroid 2-Related Factor 2; Stroke.

Figure 1

Mean percentage and confidence interval (CI) (error bars) of nuclear factor erythroid 2-related factor 2 (Nrf2) expression in the cortex (A), striatum (B), and diencephalon (C) regions in the dimethyl fumarate (DMF)-treated, vehicle, and sham groups in hemispheres ipsilateral (Ipsi) and contralateral (Contra) to middle cerebral artery occlusion (MCAO)

Figure 2

Mean percentage and confidence interval (CI) (error bars) of infarct volume in total brain (A), cortex (B), striatum (C), and diencephalon (D) regions in the dimethyl fumarate (DMF)-treated and vehicle groups

Figure 3

4′,6-diamidine-2′-phenylindole dihydrochloride (DAPI) for nuclear staining (blue), nuclear factor erythroid 2-related factor 2 (Nrf2) (green), and merged DAPI/Nrf2 in the cortex of sham, vehicle, and dimethyl fumarate (DMF)-treated groups; the increased number of nuclei and Nrf2 expression can be seen in the DMF-treated group in comparison with vehicle group.