title: Increased blood-brain barrier permeability and brain edema after focal cerebral ischemia induced by hyperlipidemia: role of lipid peroxidation and calpain-1/2, matrix metalloproteinase-2/9, and RhoA overactivation.
abstract: OBJECTIVE
  Hyperlipidemia is a highly prevalent risk factor for ischemic stroke. Its impact on brain injury and blood-brain barrier permeability, so far, has not been assessed in animal models of ischemic stroke.
  
  
  METHODS
  Wild-type and apolipoprotein E(-/-) mice, fed with normal or cholesterol-rich high-fat food, were subjected to 30 minutes of middle cerebral artery occlusion. Ischemic injury, brain edema, IgG extravasation, lipid peroxidation, calpain-1/2, matrix metalloproteinase-2/9, and RhoA activation, and occludin expression were evaluated 24 hours after reperfusion.
  
  
  RESULTS
  Cholesterol-rich food, but not apolipoprotein E deficiency, increased IgG extravasation and brain edema without influencing infarct area and the density of DNA fragmented cells. Increased lipid peroxidation and low-density lipoprotein oxidation were noticed in the brain of hyperlipidemic mice and were associated with increased activation of calpain-1/2 and matrix metalloproteinase-2/9, overactivation of RhoA and its guanine exchange factor leukemia-associated guanine exchange factor , and downregulation of the tight junction protein occludin in cerebral microvessels.
  
  
  CONCLUSIONS
  That postischemic blood-brain barrier permeability and brain edema are increased during hyperlipidemia points toward the importance of the recognition and adequate treatment of this highly prevalent condition. Translational studies should more adequately mimic risk factors prevalent in human stroke.
authors.affiliation: Department of Neurology, University Hospital Essen, Hufelandstrasse 55, D-45122 Essen, Germany.
authors.forename: Ayman
authors.initials: A
authors.lastname: ElAli
authors.forename: Thorsten R
authors.initials: TR
authors.lastname: Doeppner
authors.forename: Anil
authors.initials: A
authors.lastname: Zechariah
authors.forename: Dirk M
authors.initials: DM
authors.lastname: Hermann
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000201:enzymology*; D001929:Brain Edema / Q000201:enzymology* / Q000209:etiology / Q000473:pathology; D002545:Brain Ischemia / Q000201:enzymology* / Q000473:pathology; D002154:Calpain / Q000378:metabolism; D002199:Capillary Permeability / Q000502:physiology*; D004789:Enzyme Activation / Q000502:physiology; D006949:Hyperlipidemias / Q000150:complications / Q000201:enzymology* / Q000473:pathology; D015227:Lipid Peroxidation / Q000502:physiology*; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020741:rho GTP-Binding Proteins / Q000378:metabolism; D020742:rhoA GTP-Binding Protein
chemical_list: D002154:Calpain; C112682:Capn1 protein, mouse; C569870:CAPN2 protein, human; D020778:Matrix Metalloproteinase 2; C522362:Mmp2 protein, mouse; D020780:Matrix Metalloproteinase 9; C501830:Mmp9 protein, mouse; C526380:RhoA protein, mouse; D020741:rho GTP-Binding Proteins; D020742:rhoA GTP-Binding Protein