Size-dependent blood-brain barrier opening demonstrated with [ 14C]sucrose and a 200,000-da [ 3H]dextran

Abstract

The reclosure of the blood-brain barrier following osmotic opening was investigated by determining the product of permeability times surface area for two neutral, water-soluble compounds differing widely in molecular size. [ 14C]Sucrose ( M r 340 Da, radius 5 Å) and [ 3H]dextran ( M r 200,000 Da, radius 100 Å) were simultaneously injected i.v., and their regional permeability times surface areas were calculated at 6, 10, 35, and 55 min after the blood-brain barrier was opened by a 30-s infusion of 1.8 m l(+)-arabinose into the right external carotid artery. The control permeability times surface area product was about 10 −5 cm 3 s −1 g −1 brain for sucrose and negligible for dextran. It increased to 4 × 10 −4 cm 3 s −1 g −1 brain for sucrose and dextran, respectively, at 6 min after opening of the blood-brain barrier. Thereafter, permeability-surface area products for both substances declined. Dextran had significantly lower ( P < 0.05) values than sucrose at all times. The ratios of permeability times surface areas of [ 14C]sucrose to those to [ 3H]dextran were consistent with restricted diffusion through pores or slits at 35 and 55 min after blood-brain barrier opening, but at 6 and 10 min these ratios were less than the ratio of their free diffusion coefficients, indicative of bulk fluid flow with solute drag from blood to brain. A previously measured increase in brain water content following opening of the blood-brain barrier together with the present results, suggest the creation of slits approximately 400 Å in width after osmotic treatment. Reduction in bulk fluid flow from blood to brain appears to be the major cause for the reduction of permeability times surface areas for both sucrose and dextran as the blood-brain barrier recloses.