title: Dimethylfumarate alleviates early brain injury and secondary cognitive deficits after experimental subarachnoid hemorrhage via activation of Keap1-Nrf2-ARE system.
abstract: OBJECTIVE
  Oxidative stress and the inflammatory response are thought to promote brain damage in the setting of subarachnoid hemorrhage (SAH). Previous reports have shown that dimethylfumarate (DMF) can activate the Kelch-like ECH-associated protein 1-nuclear factor erythroid 2-related factor 2-antioxidant-responsive element (Keap1-Nrf2-ARE) system in vivo and in vitro, which leads to the downregulation of oxidative stress and inflammation. The aim of this study was to evaluate the potential neuroprotective effect of DMF on SAH-induced brain injury in rats.
  
  
  METHODS
  Rats were subjected to SAH by the injection of 300 μl of autologous blood into the chiasmatic cistern. Rats in a DMF-treated group were given 15 mg/kg DMF twice daily by oral gavage for 2 days after the onset of SAH. Cortical apoptosis, neural necrosis, brain edema, blood-brain barrier impairment, learning deficits, and changes in the Keap1-Nrf2-ARE pathway were assessed.
  
  
  RESULTS
  Administration of DMF significantly ameliorated the early brain injury and learning deficits induced by SAH in this animal model. Treatment with DMF markedly upregulated the expressions of agents related to Keap1-Nrf2-ARE signaling after SAH. The inflammatory response and oxidative stress were downregulated by DMF therapy.
  
  
  CONCLUSIONS
  DMF administration resulted in abatement of the development of early brain injury and cognitive dysfunction in this prechiasmatic cistern SAH model. This result was probably mediated by the effect of DMF on the Keap1-Nrf2-ARE system.
authors.affiliation: Department of Neurosurgery and Interventional Radiology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu Province, China.
authors.forename: Yizhi
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Neurosurgery and Interventional Radiology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu Province, China.
authors.forename: Jiaoxue
authors.initials: J
authors.lastname: Qiu
authors.affiliation: Department of Neurosurgery and Interventional Radiology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu Province, China.
authors.forename: Zhong
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Department of Neurosurgery and Interventional Radiology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu Province, China.
authors.forename: Wanchun
authors.initials: W
authors.lastname: You
authors.affiliation: Department of Neurosurgery and Interventional Radiology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu Province, China.
authors.forename: Lingyun
authors.initials: L
authors.lastname: Wu
authors.affiliation: Department of Neurosurgery and Interventional Radiology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu Province, China.
authors.forename: Chengyuan
authors.initials: C
authors.lastname: Ji
authors.affiliation: Department of Neurosurgery and Interventional Radiology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu Province, China.
authors.forename: Gang
authors.initials: G
authors.lastname: Chen
mesh_terms: D000818:Animals; D061745:Antioxidant Response Elements / Q000502:physiology*; D001930:Brain Injuries / Q000188:drug therapy* / Q000209:etiology*; D003072:Cognition Disorders / Q000188:drug therapy* / Q000209:etiology*; D000069462:Dimethyl Fumarate / Q000627:therapeutic use*; D047908:Intracellular Signaling Peptides and Proteins / Q000502:physiology*; D000072019:Kelch-Like ECH-Associated Protein 1; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D013345:Subarachnoid Hemorrhage / Q000150:complications*
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; C486610:KEAP1 protein, rat; D000072019:Kelch-Like ECH-Associated Protein 1; D000069462:Dimethyl Fumarate
keywords: ARE = antioxidant-responsive element; DMF = dimethylfumarate; EBI = early brain injury; ELISA = enzyme-linked immunosorbent assay; EMSA = electrophoretic mobility shift assay; FJB = Fluoro-Jade B; GSH-Px = glutathione peroxidase; GST-α1 = glutathione S-transferase α1; HO-1 = heme oxygenase 1; IL = interleukin; Keap1 = Kelch-like ECH-associated protein 1; MDA = malondialdehyde; MWM = Morris water maze; NQO1 = quinone oxidoreductase 1; Nrf2; Nrf2 = nuclear factor erythroid 2-related factor 2; PBS = phosphate-buffered saline; SAH = subarachnoid hemorrhage; SOD = superoxide dismutase; TNFα = tumor necrosis factor–α; dimethylfumarate; subarachnoid hemorrhage; vascular disorders