title: Role of oxidized LDL and lectin-like oxidized LDL receptor-1 in cerebral vasospasm after subarachnoid hemorrhage.
abstract: OBJECTIVE
  Cerebral vasospasm after subarachnoid hemorrhage (SAH) is a serious complication. Free radicals derived from subarachnoid clotting are recognized to play an important role. Oxidized low-density lipoprotein (ox-LDL) and lectin-like oxidized LDL receptor-1 (LOX-1) have been shown to be related to the pathogenesis of atherosclerosis and may increase in cerebral arteries after SAH, due to the action of free radicals derived from a subarachnoid clot. These molecules may also affect the pathogenesis of vasospasm, generating intracellular reactive oxygen species and downregulating the expression of endothelial NO synthase (eNOS). If so, apple polyphenol might be effective in the prevention of vasospasm due to an abundant content of procyanidins, which exhibit strong radical scavenging effects, and the ability to suppress ox-LDL and LOX-1. The purposes of this study were to investigate changes in levels of ox-LDL and LOX-1 after SAH and whether administering apple polyphenol can modify cerebral vasospasm.
  
  
  METHODS
  Forty Japanese white rabbits were assigned randomly to 4 groups: an SAH group (n = 10); a shamoperation group (n = 10), which underwent intracisternal saline injection; a low-dose polyphenol group (n = 10) with SAH and oral administration of apple polyphenol at 10 mg/kg per day from Day 0 to Day 3; and a high-dose polyphenol group (n = 10) with SAH and oral administration of apple polyphenol at 50 mg/kg per day. At Day 4, the basilar artery and brain was excised from each rabbit. The degree of cerebral vasospasm was evaluated by measuring the cross-sectional area of each basilar artery, and the expression of ox-LDL, LOX-1, and eNOS was examined for each basilar artery by immunohistochemical staining and reverse transcriptase polymerase chain reaction. In addition, neuronal apoptosis in the cerebral cortex was evaluated by TUNEL.
  
  
  RESULTS
  Compared with the sham group, the expression of ox-LDL and LOX-1 in the basilar arterial wall was significantly increased in the SAH group, the expression of eNOS was significantly decreased, and the cross-sectional area of basilar artery was significantly decreased. Compared with the SAH group, the cross-sectional area of basilar artery was increased in the polyphenol groups, together with the decreased expression of ox-LDL and LOX-1 and the increased expression of eNOS. In the high-dose polyphenol group, those changes were statistically significant compared with the SAH group. In the low-dose polyphenol group, those changes were smaller than in the high-dose polyphenol group. No apoptosis and no changes were seen in the cerebral cortex in all groups.
  
  
  CONCLUSIONS
  This is the first study suggesting that ox-LDL and LOX-1 increase due to SAH and that they may play a role in the pathogenesis of vasospasm. It is assumed that procyanidins in apple polyphenol may inhibit a vicious cycle of ox-LDL, LOX-1, and ROS in a dose-dependent manner. Apple polyphenol is a candidate for preventive treatment of cerebral vasospasm.
authors.affiliation: Department of Neurosurgery, Hirosaki University School of Medicine, Hirosaki, Japan.
authors.forename: Naoya
authors.initials: N
authors.lastname: Matsuda
authors.forename: Hiroki
authors.initials: H
authors.lastname: Ohkuma
authors.forename: Masato
authors.initials: M
authors.lastname: Naraoka
authors.forename: Akira
authors.initials: A
authors.lastname: Munakata
authors.forename: Norihito
authors.initials: N
authors.lastname: Shimamura
authors.forename: Kenichiro
authors.initials: K
authors.lastname: Asano
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001488:Basilar Artery / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D002726:Chlorogenic Acid / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D005260:Female; D005419:Flavonoids / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D008077:Lipoproteins, LDL / Q000187:drug effects / Q000378:metabolism*; D023421:Models, Animal; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D044945:Proanthocyanidins / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D011817:Rabbits; D017382:Reactive Oxygen Species / Q000378:metabolism; D051127:Scavenger Receptors, Class E / Q000187:drug effects / Q000378:metabolism*; D013345:Subarachnoid Hemorrhage / Q000150:complications*; D013634:Tannins / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D020301:Vasospasm, Intracranial / Q000209:etiology* / Q000378:metabolism* / Q000517:prevention & control
chemical_list: D005419:Flavonoids; D008077:Lipoproteins, LDL; D044945:Proanthocyanidins; D017382:Reactive Oxygen Species; D051127:Scavenger Receptors, Class E; D013634:Tannins; C526219:apple polyphenol extract; C099252:oxidized low density lipoprotein; D002726:Chlorogenic Acid; D052250:Nitric Oxide Synthase Type III
keywords: GAPDH = glyceraldehyde-3-phosphate-dehydrogenase; LDL = low-density lipoprotein; LOX-1 = lectin-like oxidized LDL receptor-1; NIH = National Institutes of Health; NO = nitric oxide; PBS = phosphate-buffered saline; ROS = reactive oxygen species; RT-PCR = reverse transcriptase polymerase chain reaction; SAH = subarachnoid hemorrhage; TUNEL = terminal deoxynucleotidyl transferase–mediated deoxyuridine triphosphate nick-end labeling; cerebral vasospasm; eNOS = endothelial NO synthase; free radical; lectin-like oxidized LDL receptor-1; ox-LDL = oxidized LDL; oxidized low-density lipoprotein; polyphenol; subarachnoid hemorrhage; vascular disorders