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.
Keywords:
Dimethyl fumarate; HO-1; Monomethyl fumarate; Nrf2; Stroke.
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Animals
-
Brain Edema / drug therapy
-
Brain Edema / etiology
-
Calcium-Binding Proteins / metabolism
-
Dimethyl Fumarate / pharmacology*
-
Dimethyl Fumarate / therapeutic use*
-
Disease Models, Animal
-
Dose-Response Relationship, Drug
-
Fumarates / pharmacology*
-
Fumarates / therapeutic use*
-
Glial Fibrillary Acidic Protein / metabolism
-
Glutathione / metabolism
-
Immunosuppressive Agents / pharmacology
-
Immunosuppressive Agents / therapeutic use
-
Infarction, Middle Cerebral Artery / diagnostic imaging
-
Infarction, Middle Cerebral Artery / drug therapy*
-
Maleates / pharmacology*
-
Maleates / therapeutic use*
-
Malondialdehyde / metabolism
-
Mice
-
Mice, Inbred C57BL
-
Microfilament Proteins / metabolism
-
NF-E2-Related Factor 2 / deficiency
-
NF-E2-Related Factor 2 / genetics
-
Neurologic Examination
-
Neuroprotective Agents / pharmacology
-
Neuroprotective Agents / therapeutic use
-
Oxidative Stress / drug effects
-
Recovery of Function / drug effects*
-
Reperfusion Injury / drug therapy
-
Time Factors
Substances
-
Aif1 protein, mouse
-
Calcium-Binding Proteins
-
Fumarates
-
Glial Fibrillary Acidic Protein
-
Immunosuppressive Agents
-
Maleates
-
Microfilament Proteins
-
NF-E2-Related Factor 2
-
Neuroprotective Agents
-
Nfe2l2 protein, mouse
-
citraconic acid
-
Malondialdehyde
-
Dimethyl Fumarate
-
Glutathione