title: Inhibition of protein kinase Cβ reverses increased blood-brain barrier permeability during hyperglycemic stroke and prevents edema formation in vivo.
abstract: OBJECTIVE
  We investigated the effect of circulating factors and protein kinase Cβ on blood-brain barrier permeability and edema during hyperglycemic stroke.
  
  
  METHODS
  Male Wistar rats that were hyperglycemic by streptozotocin (50 mg/kg) for 5 to 6 days underwent middle cerebral artery occlusion (MCAO) for 2 hours with 2 hours of reperfusion. Blood-brain barrier permeability was measured in middle cerebral arteries that were ischemic (MCAO) or nonischemic (CTL) and perfused with plasma (20% in buffer) from MCAO or CTL animals. A separate set of MCAO vessels was perfused with the protein kinase Cβ inhibitor CGP53353 (0.5 μmol/L) and permeability measured. Lastly, hyperglycemic rats were treated intravenously with CGP53353 (10 or 100 μg/kg or vehicle 15 minutes before reperfusion and edema formation measured by wet:dry weights (n=6/group).
  
  
  RESULTS
  MCAO vessels had increased permeability compared with controls regardless of the plasma perfusate. Permeability (water flux, μm(3)×10(8)) of CTL vessel/CTL plasma (n=8), CTL vessel/MCAO plasma (n=7), MCAO vessel/CTL plasma (n=6), and MCAO vessel/MCAO plasma (n=6) was 0.98±0.11, 1.13±0.07, 1.36±0.02, and 1.34±0.06; P<0.01). Inhibition of protein kinase Cβ in MCAO vessels (n=6) reversed the increase in permeability (0.92±0.1; P<0.01). In vivo, hyperglycemia increased edema versus normoglycemia after MCAO (water content=78.84%±0.11% versus 81.38%±0.21%; P<0.01). Inhibition of protein kinase Cβ with 10 or 100 μg/kg CGP53353 during reperfusion prevented the increased edema in hyperglycemic animals (water content=79.54%±0.56% and 79.99%±0.43%; P<0.01 versus vehicle).
  
  
  CONCLUSIONS
  These results suggest that the pronounced vasogenic edema that occurs during hyperglycemic stroke is mediated in large part by activation of protein kinase Cβ.
authors.affiliation: Department of Neurology, University of Vermont College of Medicine, Burlington, VT 05405, USA. Marilyn.Cipolla@uvm.edu
authors.forename: Marilyn J
authors.initials: MJ
authors.lastname: Cipolla
authors.forename: Quillan
authors.initials: Q
authors.lastname: Huang
authors.forename: Julie G
authors.initials: JG
authors.lastname: Sweet
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000201:enzymology*; D001929:Brain Edema / Q000201:enzymology* / Q000517:prevention & control*; D002199:Capillary Permeability / Q000187:drug effects / Q000502:physiology; D006943:Hyperglycemia / Q000188:drug therapy / Q000201:enzymology*; D008297:Male; D010797:Phthalimides / Q000494:pharmacology / Q000627:therapeutic use; D011493:Protein Kinase C / Q000037:antagonists & inhibitors* / Q000502:physiology; D064546:Protein Kinase C beta; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D051381:Rats; D017208:Rats, Wistar; D020521:Stroke / Q000188:drug therapy / Q000201:enzymology*
chemical_list: D010797:Phthalimides; D047428:Protein Kinase Inhibitors; D011493:Protein Kinase C; D064546:Protein Kinase C beta; C098874:4,5-dianilinophthalimide