Inhibition of Protein Kinase Cβ Reverses Increased Blood-Brain Barrier Permeability During Hyperglycemic Stroke and Prevents Edema Formation In Vivo

Background and Purpose-We investigated the effect of circulating factors and protein kinase C beta 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 C beta inhibitor CGP53353 (0.5 mu mol/L) and permeability measured. Lastly, hyperglycemic rats were treated intravenously with CGP53353 (10 or 100 mu g/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, mu m(3) x 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 C beta 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 C beta with 10 or 100 mu g/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 C beta. (Stroke. 2011; 42:3252-3257.)