Abstract
Oxidative stress plays an important role in cerebral ischemia–reperfusion injury. Dimethyl fumarate (DMF) and its primary metabolite monomethyl fumarate (MMF) are antioxidant agents that can activate the nuclear factor erythroid-2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) pathway and induce the expression of antioxidant proteins. Here, we evaluated the impact of DMF and MMF on ischemia-induced brain injury and whether the Nrf2 pathway mediates the effects provided by DMF and MMF in cerebral ischemia–reperfusion injury. Using a mouse model of transient focal brain ischemia, we show that DMF and MMF significantly reduce neurological deficits, infarct volume, brain edema, and cell death. Further, DMF and MMF suppress glial activation following brain ischemia. Importantly, the protection of DMF and MMF was mostly evident during the subacute stage and was abolished in Nrf2−/− mice, indicating that the Nrf2 pathway is required for the beneficial effects of DMF and MMF. Together, our data indicate that DMF and MMF have therapeutic potential in cerebral ischemia–reperfusion injury and their protective role is likely mediated by the Nrf2 pathway.Electronic supplementary materialThe online version of this article (doi:10.1007/s12975-016-0496-0) contains supplementary material, which is available to authorized users.
Highlights
Stroke is the second leading cause of death globally and composed of hemorrhagic and ischemic stroke, with the latter being more common and resulting from disruption of blood supply to the brain [1, 2]
On day 1 post-middle cerebral artery occlusion (MCAO) ischemia–reperfusion injury, there was no statistical difference in modified neurological severity score (mNSS) between groups of MCAO mice treated with vehicle control, Dimethyl fumarate (DMF) (30, 45 mg/kg), or monomethyl fumarate (MMF) (30, 45 mg/kg) groups
The improvement of neurobehavioral function with DMF or MMF treatment was dose-dependent with a better outcome in mice treated with the relatively higher dose of DMF (45 mg/kg) or MMF (45 mg/kg) as compared with those treated with the lower dose of DMF (30 mg/kg) or MMF (30 mg/kg) body weight, respectively (Fig. 1d)
Summary
Stroke is the second leading cause of death globally and composed of hemorrhagic and ischemic stroke, with the latter being more common and resulting from disruption of blood supply to the brain [1, 2]. (2016) 7:535–547 or medically induced recanalization after cerebral ischemia can cause tissue injury which in turn contributes to worsening neurological status as well as increased morbidity and mortality in patients with acute ischemic stroke [5]. Some pharmacological agents have been studied to address ischemia–reperfusion injury by blocking reactive oxygen species (ROS) and neuronal excitotoxicity [9, 10]. These agents have far failed to demonstrate efficacy in clinical trials [11, 12]. It remains an urgent need to develop neuroprotective strategies targeting multiple key steps in the biochemical cascade of ischemia–reperfusion injury
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