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 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, μm3×108) 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.
- Received April 20, 2011.
- Revision received May 2, 2011.
- Accepted May 12, 2011.
- © 2011 American Heart Association, Inc.