title: Protecting against cerebrovascular injury: contributions of 12/15-lipoxygenase to edema formation after transient focal ischemia.
abstract: OBJECTIVE
  The concept of the neurovascular unit suggests that effects on brain vasculature must be considered if neuroprotection is to be achieved in stroke. We previously reported that 12/15-lipoxygenase (12/15-LOX) is upregulated in the peri-infarct area after middle cerebral artery occlusion in mice, and 12/15-LOX contributes to brain damage after ischemia-reperfusion. The current study was designed to investigate 12/15-LOX involvement in vascular injury in the ischemic brain.
  
  
  METHODS
  In cell culture, a human brain microvascular endothelial cell line was subjected to either hypoxia or H(2)O(2)-induced oxidative stress with or without lipoxygenase inhibitors. For in vivo studies, mice were subjected to 90 minutes middle cerebral artery occlusion, and the effects of either 12/15-LOX gene knockout or treatment with lipoxygenase inhibitors were compared. Expression of 12/15-LOX and claudin-5 as well as extravasation of immunoglobulin G were detected by immunohistochemistry. Edema was measured as water content of brain hemispheres according to the wet-dry weight method.
  
  
  RESULTS
  Brain endothelial cells were protected against hypoxia and H(2)O(2) by the lipoxygenase inhibitor baicalein. After focal ischemia, 12/15-LOX was increased in neurons and endothelial cells. The vascular tight junction protein claudin-5 underwent extensive degradation in the peri-infarct area, which was partially prevented by the lipoxygenase inhibitor baicalein. Leakage of immunoglobulin G into the brain parenchyma was significantly reduced in 12/15-LOX knockout mice as well as wild-type mice treated with baicalein. Likewise, brain edema was significantly ameliorated.
  
  
  CONCLUSIONS
  12/15-LOX may contribute to ischemic brain damage not just by causing neuronal cell death, but also by detrimental effects on the brain microvasculature. 12/15-LOX inhibitors may thus be effective as both neuroprotectants and vasculoprotectants.
authors.affiliation: Massachusetts General Hospital, Neuroprotection Research Laboratory, 149 13th Street, R. 2401, Charlestown, MA 02129, USA.
authors.forename: Guang
authors.initials: G
authors.lastname: Jin
authors.forename: Ken
authors.initials: K
authors.lastname: Arai
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Murata
authors.forename: Sophia
authors.initials: S
authors.lastname: Wang
authors.forename: Monique F
authors.initials: MF
authors.lastname: Stins
authors.forename: Eng H
authors.initials: EH
authors.lastname: Lo
authors.forename: Klaus
authors.initials: K
authors.lastname: van Leyen
mesh_terms: D000818:Animals; D001092:Arachidonate 12-Lipoxygenase / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D001093:Arachidonate 15-Lipoxygenase / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000378:metabolism; D001929:Brain Edema / Q000201:enzymology* / Q000503:physiopathology / Q000517:prevention & control; D020520:Brain Infarction / Q000188:drug therapy / Q000201:enzymology* / Q000503:physiopathology; D002545:Brain Ischemia / Q000188:drug therapy / Q000201:enzymology* / Q000503:physiopathology; D002478:Cells, Cultured; D062507:Claudin-5; D019610:Cytoprotection / Q000187:drug effects; D042783:Endothelial Cells / Q000187:drug effects / Q000201:enzymology; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D044950:Flavanones / Q000627:therapeutic use*; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D007074:Immunoglobulin G / Q000378:metabolism; D002546:Ischemic Attack, Transient / Q000188:drug therapy / Q000201:enzymology* / Q000503:physiopathology; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D019108:Tight Junctions / Q000187:drug effects / Q000378:metabolism
chemical_list: C475064:12-15-lipoxygenase; C107466:CLDN5 protein, human; D062507:Claudin-5; D004791:Enzyme Inhibitors; D044950:Flavanones; D007074:Immunoglobulin G; D008565:Membrane Proteins; C006680:baicalein; D006861:Hydrogen Peroxide; D001092:Arachidonate 12-Lipoxygenase; D001093:Arachidonate 15-Lipoxygenase