Dimethyl Fumarate and Monomethyl Fumarate Promote Post-Ischemic Recovery in Mice.
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.
Department of Neurology, Tianjin Neurological Institute, Tianjin Medical University General Hospital, Tianjin, 300052, China.
Yang
Y
Yao
The State Key Laboratory of Experimental Hematology, Chinese Academy of Medical Sciences and Peking Union Medical College, 288 Nanjing Road, Tianjin, 300020, China.
Weimin
W
Miao
Department of Neurology, Tianjin Neurological Institute, Tianjin Medical University General Hospital, Tianjin, 300052, China.
Zhijia
Z
Liu
Department of Radiology, Tianjin Neurological Institute, Tianjin Medical University General Hospital, Tianjin, 300052, China.
Wei
W
Han
Department of Neurology, Tianjin Neurological Institute, Tianjin Medical University General Hospital, Tianjin, 300052, China.
Kaibin
K
Shi
Department of Neurology, Tianjin Neurological Institute, Tianjin Medical University General Hospital, Tianjin, 300052, China.
Yi
Y
Shen
Department of Neurology, Tianjin Neurological Institute, Tianjin Medical University General Hospital, Tianjin, 300052, China.
Handong
H
Li
Department of Neurology, Tianjin Neurological Institute, Tianjin Medical University General Hospital, Tianjin, 300052, China.|Department of Neurology, Barrow Neurological Institute, St. Joseph's Hospital and Medical Center, Phoenix, AZ, 85013, USA.
Qiang
Q
Liu
Department of Neurology, Tianjin Neurological Institute, Tianjin Medical University General Hospital, Tianjin, 300052, China.
Ying
Y
Fu
Neurology and Neuroscience Associates, Unity Health Network, Akron, OH, USA.
DeRen
D
Huang
Department of Neurology, Tianjin Neurological Institute, Tianjin Medical University General Hospital, Tianjin, 300052, China. fshi@tmu.edu.cn.|Department of Neurology, Barrow Neurological Institute, St. Joseph's Hospital and Medical Center, Phoenix, AZ, 85013, USA. fshi@tmu.edu.cn.
Fu-Dong
FD
Shi
D000818:Animals; D001929:Brain Edema / Q000188:drug therapy / Q000209:etiology; D002135:Calcium-Binding Proteins / Q000378:metabolism; D000069462:Dimethyl Fumarate / Q000494:pharmacology* / Q000627:therapeutic use*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005650:Fumarates / Q000494:pharmacology* / Q000627:therapeutic use*; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D007166:Immunosuppressive Agents / Q000494:pharmacology / Q000627:therapeutic use; D020244:Infarction, Middle Cerebral Artery / Q000000981:diagnostic imaging / Q000188:drug therapy*; D008298:Maleates / Q000494:pharmacology* / Q000627:therapeutic use*; D008315:Malondialdehyde / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008840:Microfilament Proteins / Q000378:metabolism; D051267:NF-E2-Related Factor 2 / Q000172:deficiency / Q000235:genetics; D009460:Neurologic Examination; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use; D018384:Oxidative Stress / Q000187:drug effects; D020127:Recovery of Function / Q000187:drug effects*; D015427:Reperfusion Injury / Q000188:drug therapy; D013997:Time Factors
C491049:Aif1 protein, mouse; D002135:Calcium-Binding Proteins; D005650:Fumarates; D005904:Glial Fibrillary Acidic Protein; D007166:Immunosuppressive Agents; D008298:Maleates; D008840:Microfilament Proteins; D051267:NF-E2-Related Factor 2; D018696:Neuroprotective Agents; C495636:Nfe2l2 protein, mouse; C073341:citraconic acid; D008315:Malondialdehyde; D000069462:Dimethyl Fumarate; D005978:Glutathione
Dimethyl fumarate; HO-1; Monomethyl fumarate; Nrf2; Stroke