title: Nobiletin promotes antioxidant and anti-inflammatory responses and elicits protection against ischemic stroke in vivo.
abstract: BACKGROUND
  Post-ischemic oxidative stress and inflammation play pivotal roles in the pathogenesis of ischemic stroke and may represent therapeutic targets. Nobiletin (NOB) has been reported to elicit a variety of biological effects through its anti-oxidant and anti-inflammatory properties. Our previous study has demonstrated the beneficial effect of NOB in ischemic stroke, but the underlying mechanisms remain poorly defined. We therefore further investigated the role of NOB in cerebral ischemia and its potential mechanisms.
  
  
  METHODS
  Adult male Sprague-Dawley rats were randomly assigned to five groups: Sham (sham-operated+0.05% Tween-80), permanent middle cerebral artery occlusion (pMCAO+0.9% saline), Vehicle (pMCAO+0.05% Tween-80), NOB-L (pMCAO+NOB 10mg/kg) and NOB-H (pMCAO+NOB 25mg/kg) groups. Rats were pre-administered intraperitoneally once daily for 3 days prior to ischemia and then received once again immediately after surgery. Neurological deficit, brain edema and infarct volume were evaluated at 24h after stroke. Immunohistochemistry, western blot and RT-qPCR were used to detect the expression of Nrf2, HO-1, SOD1, NF-κB and MMP-9. SOD1, GSH and MDA were measured by spectrophotometer.
  
  
  RESULTS
  Compared with Vehicle group, neurological deficits and brain edema were relieved in NOB-H group, infarct volume was lessened in both NOB-L and NOB-H groups (P<0.05). NOB significantly increased the expression of Nrf2, HO-1, SOD1 and GSH, while decreased the levels of NF-κB, MMP-9 and MDA (P<0.05).
  
  
  CONCLUSIONS
  NOB may have a neuroprotective effect on cerebral ischemia, and this protection may be through upregulating Nrf2, HO-1 and downregulating NF-κB expression.
authors.affiliation: Department of Neurology, Second Hospital of Hebei Medical University, Shijiazhuang, Hebei 050000, PR China; Hebei Collaborative Innovation Center for Cardio-cerebrovascular Disease, Shijiazhuang, Hebei 050000, PR China; Hebei Key Laboratory of Vascular Homeostasis, Shijiazhuang, Hebei 050000, PR China.
authors.forename: Lan
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Neurology, Second Hospital of Hebei Medical University, Shijiazhuang, Hebei 050000, PR China; Hebei Collaborative Innovation Center for Cardio-cerebrovascular Disease, Shijiazhuang, Hebei 050000, PR China; Hebei Key Laboratory of Vascular Homeostasis, Shijiazhuang, Hebei 050000, PR China. Electronic address: zhang6xj@aliyun.com.
authors.forename: Xiangjian
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Neurology, Second Hospital of Hebei Medical University, Shijiazhuang, Hebei 050000, PR China; Hebei Collaborative Innovation Center for Cardio-cerebrovascular Disease, Shijiazhuang, Hebei 050000, PR China; Hebei Key Laboratory of Vascular Homeostasis, Shijiazhuang, Hebei 050000, PR China.
authors.forename: Cong
authors.initials: C
authors.lastname: Zhang
authors.affiliation: Department of Neurology, Second Hospital of Hebei Medical University, Shijiazhuang, Hebei 050000, PR China.
authors.forename: Xue
authors.initials: X
authors.lastname: Bai
authors.affiliation: Department of Neurology, Second Hospital of Hebei Medical University, Shijiazhuang, Hebei 050000, PR China; Hebei Collaborative Innovation Center for Cardio-cerebrovascular Disease, Shijiazhuang, Hebei 050000, PR China; Hebei Key Laboratory of Vascular Homeostasis, Shijiazhuang, Hebei 050000, PR China.
authors.forename: Jian
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Neurology, Second Hospital of Hebei Medical University, Shijiazhuang, Hebei 050000, PR China; Hebei Collaborative Innovation Center for Cardio-cerebrovascular Disease, Shijiazhuang, Hebei 050000, PR China; Hebei Key Laboratory of Vascular Homeostasis, Shijiazhuang, Hebei 050000, PR China.
authors.forename: Xumeng
authors.initials: X
authors.lastname: Zhao
authors.affiliation: Department of Neurology, Second Hospital of Hebei Medical University, Shijiazhuang, Hebei 050000, PR China; Hebei Collaborative Innovation Center for Cardio-cerebrovascular Disease, Shijiazhuang, Hebei 050000, PR China; Hebei Key Laboratory of Vascular Homeostasis, Shijiazhuang, Hebei 050000, PR China.
authors.forename: Linyu
authors.initials: L
authors.lastname: Chen
authors.affiliation: Department of Neurology, Second Hospital of Hebei Medical University, Shijiazhuang, Hebei 050000, PR China; Hebei Collaborative Innovation Center for Cardio-cerebrovascular Disease, Shijiazhuang, Hebei 050000, PR China; Hebei Key Laboratory of Vascular Homeostasis, Shijiazhuang, Hebei 050000, PR China.
authors.forename: Lina
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Neurology, Second Hospital of Hebei Medical University, Shijiazhuang, Hebei 050000, PR China; Hebei Collaborative Innovation Center for Cardio-cerebrovascular Disease, Shijiazhuang, Hebei 050000, PR China; Hebei Key Laboratory of Vascular Homeostasis, Shijiazhuang, Hebei 050000, PR China.
authors.forename: Chunhua
authors.initials: C
authors.lastname: Zhu
authors.affiliation: Department of Neurology, Second Hospital of Hebei Medical University, Shijiazhuang, Hebei 050000, PR China; Hebei Collaborative Innovation Center for Cardio-cerebrovascular Disease, Shijiazhuang, Hebei 050000, PR China; Hebei Key Laboratory of Vascular Homeostasis, Shijiazhuang, Hebei 050000, PR China.
authors.forename: Lili
authors.initials: L
authors.lastname: Cui
authors.affiliation: Hebei Collaborative Innovation Center for Cardio-cerebrovascular Disease, Shijiazhuang, Hebei 050000, PR China; Hebei Key Laboratory of Vascular Homeostasis, Shijiazhuang, Hebei 050000, PR China.
authors.forename: Rong
authors.initials: R
authors.lastname: Chen
authors.affiliation: Department of Neurology, Second Hospital of Hebei Medical University, Shijiazhuang, Hebei 050000, PR China.
authors.forename: Ting
authors.initials: T
authors.lastname: Zhao
authors.affiliation: Department of Neurology, Second Hospital of Hebei Medical University, Shijiazhuang, Hebei 050000, PR China; Hebei Collaborative Innovation Center for Cardio-cerebrovascular Disease, Shijiazhuang, Hebei 050000, PR China; Hebei Key Laboratory of Vascular Homeostasis, Shijiazhuang, Hebei 050000, PR China.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Zhao
mesh_terms: D000818:Animals; D008297:Male; D051381:Rats; D000975:Antioxidants / Q000627:therapeutic use; D001929:Brain Edema / Q000188:drug therapy / Q000209:etiology; D020520:Brain Infarction / Q000188:drug therapy / Q000209:etiology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004660:Encephalitis / Q000188:drug therapy / Q000209:etiology; D047309:Flavones / Q000627:therapeutic use; D007839:Functional Laterality; D005786:Gene Expression Regulation / Q000187:drug effects; D051547:Heme Oxygenase-1 / Q000235:genetics / Q000378:metabolism; D020244:Infarction, Middle Cerebral Artery / Q000150:complications / Q000188:drug therapy; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism; D009422:Nervous System Diseases / Q000188:drug therapy / Q000209:etiology; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D000072105:Superoxide Dismutase-1 / Q000235:genetics / Q000378:metabolism; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism
chemical_list: D000975:Antioxidants; D047309:Flavones; D051547:Heme Oxygenase-1; D020780:Matrix Metalloproteinase 9; C572337:Mmp9 protein, rat; D016328:NF-kappa B; C008661:nobiletin; C000606292:Sod1 protein, rat; D000072105:Superoxide Dismutase-1; D051267:NF-E2-Related Factor 2; C495637:Nfe2l2 protein, rat
keywords: HO-1; Ischemic stroke; NF-κB; Neuroprotection; Nobiletin; Nrf2