title: Pinocembrin protects rats against cerebral ischemic damage through soluble epoxide hydrolase and epoxyeicosatrienoic acids.
abstract: OBJECTIVE
  To investigate the relationship between cerebroprotection of pinocembrin and epoxyeicosatrienoic acids (EETs) and their regulating enzyme soluble epoxide hydrolase (sEH).
  
  
  METHODS
  Rats underwent middle cerebral artery occlusion (MCAO) to mimic permanent focal ischemia, and pinocembrin was administrated via tail vein injection at 10 min, 4 h, 8 h and 23 h after MCAO. After 24 MCAO, rats were re-anesthetized, and the blood and brain were harvested and analyzed.
  
  
  RESULTS
  Pinocembrin displayed significant protective effects on MCAO rats indicated by reduced neurological deficits and infarct volume. Importantly, co-administration of 0.2 mg·kg(-1) 14, 15-EEZE, a putative selective EET antagonist, weakened the beneficial effects of pinocembrin. 14, 15-EET levels in the blood and brain of rats after 24 h MCAO were elevated in the presence of pinocembrin. In an assay for hydrolase activity, pinocembrin significantly lowered brain sEH activity of MCAO rats and inhibited recombinant human sEH activity in a concentration-dependent manner (IC50, 2.58 μmol·L(-1)). In addition, Western blot and immunohistochemistry analysis showed that pinocembrin at doses of 10 mg·kg(-1) and 30 mg·kg(-1) significantly down-regulated sEH protein in rat brain, especially the hippocampus CA1 region of MCAO rats.
  
  
  CONCLUSIONS
  Inhibiting sEH and then increasing the potency of EETs may be one of the mechanisms through which pinocembrin provides cerebral protection.
authors.affiliation: Beijing Key Laboratory of Drug Target Identification and Drug Screening, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.
authors.forename: Shou-Bao
authors.initials: SB
authors.lastname: Wang
authors.forename: Xiao-Bin
authors.initials: XB
authors.lastname: Pang
authors.forename: Mei
authors.initials: M
authors.lastname: Gao
authors.forename: Lian-Hua
authors.initials: LH
authors.lastname: Fang
authors.forename: Guan-Hua
authors.initials: GH
authors.lastname: Du
mesh_terms: D000818:Animals; D001095:Arachidonic Acids / Q000378:metabolism*; D001921:Brain / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D002545:Brain Ischemia / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control*; D004195:Disease Models, Animal; D004851:Epoxide Hydrolases / Q000235:genetics / Q000378:metabolism*; D044950:Flavanones / Q000008:administration & dosage*; D006801:Humans; D008297:Male; D020011:Protective Agents / Q000008:administration & dosage*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D001095:Arachidonic Acids; D044950:Flavanones; D020011:Protective Agents; C016063:pinocembrin; D004851:Epoxide Hydrolases