title: Bexarotene reduces blood-brain barrier permeability in cerebral ischemia-reperfusion injured rats.
abstract: BACKGROUND
  Matrix metalloproteinase-9 (MMP-9) over-expression disrupts the blood-brain barrier (BBB) in the ischemic brain. The retinoid X receptor agonist bexarotene suppresses MMP-9 expression in endothelial cells and displays neuroprotective effects. Therefore, we hypothesized that bexarotene may have a beneficial effect on I/R-induced BBB dysfunction.
  
  
  METHODS
  A total of 180 rats were randomized into three groups (n = 60 each): (i) a sham-operation group, (ii) a cerebral ischemia-reperfusion (I/R) group, and (iii) an I/R+bexarotene group. Brain water content was measured by the dry wet weight method. BBB permeability was analyzed by Evans Blue staining and the magnetic resonance imaging contrast agent Omniscan. MMP-9 mRNA expression, protein expression, and activity were assessed by reverse transcription polymerase chain reaction, Western blotting, and gelatin zymography, respectively. Apolipoprotein E (apoE), claudin-5, and occludin expression were analyzed by Western blotting.
  
  
  RESULTS
  After 24 h, 48 h, and 72 h post-I/R, several effects were observed with bexarotene administration: (i) brain water content and BBB permeability were significantly reduced; (ii) MMP-9 mRNA and protein expression as well as activity were significantly decreased; (iii) claudin-5 and occludin expression were significantly increased; and (iv) apoE expression was significantly increased.
  
  
  CONCLUSIONS
  Bexarotene decreases BBB permeability in rats with cerebral I/R injury. This effect may be due in part to bexarotene's upregulation of apoE expression, which has been previously shown to reduce BBB permeability through suppressing MMP-9-mediated degradation of the tight junction proteins claudin-5 and occludin. This work offers insight to aid future development of therapeutic agents for cerebral I/R injury in human patients.
authors.affiliation: Chongqing Key Laboratory of Biochemistry and Molecular Pharmacology, College of Pharmacy, Chongqing Medical University, Chongqing 400016, China.
authors.forename: Lu
authors.initials: L
authors.lastname: Xu
authors.affiliation: Chongqing Key Laboratory of Biochemistry and Molecular Pharmacology, College of Pharmacy, Chongqing Medical University, Chongqing 400016, China.
authors.forename: Fang
authors.initials: F
authors.lastname: Cao
authors.affiliation: Chongqing Key Laboratory of Biochemistry and Molecular Pharmacology, College of Pharmacy, Chongqing Medical University, Chongqing 400016, China.
authors.forename: Feng
authors.initials: F
authors.lastname: Xu
authors.affiliation: Chongqing Key Laboratory of Biochemistry and Molecular Pharmacology, College of Pharmacy, Chongqing Medical University, Chongqing 400016, China.
authors.forename: Baicheng
authors.initials: B
authors.lastname: He
authors.affiliation: Chongqing Key Laboratory of Biochemistry and Molecular Pharmacology, College of Pharmacy, Chongqing Medical University, Chongqing 400016, China.
authors.forename: Zhi
authors.initials: Z
authors.lastname: Dong
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000378:metabolism; D000077610:Bexarotene; D001812:Blood-Brain Barrier / Q000187:drug effects*; D002545:Brain Ischemia / Q000201:enzymology / Q000235:genetics / Q000517:prevention & control*; D062507:Claudin-5 / Q000378:metabolism; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000187:drug effects; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000235:genetics* / Q000378:metabolism; D018696:Neuroprotective Agents / Q000008:administration & dosage* / Q000494:pharmacology; D062793:Occludin / Q000378:metabolism; D051381:Rats; D013764:Tetrahydronaphthalenes / Q000008:administration & dosage* / Q000494:pharmacology
chemical_list: D001057:Apolipoproteins E; D062507:Claudin-5; C491510:Cldn5 protein, rat; D018696:Neuroprotective Agents; D062793:Occludin; C568987:Ocln protein, rat; D013764:Tetrahydronaphthalenes; D000077610:Bexarotene; D020780:Matrix Metalloproteinase 9; C572337:Mmp9 protein, rat
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