Quantitative analysis of hyperosmotic and hypothermic blood-brain barrier opening

Hyperosmotic opening of the blood-brain barrier (BBB) by mannitol is being used to enhance drug transport in human brains. Recently, cooling of the solution has been reported to have potential to open the BBB. However, the mechanism in barrier opening and closure remains elusive. We studied the rapid changes in cerebrovascular permeability after hyperosmotic and hypothermic BBB opening in rats, and then demonstrated that the Na+/Ca++ exchange blocker (KB-R7943) prolongs opening. BBB opening was attained by using intra-arterial infusion of hyperosmotic mannitol (1.6 M) and 1.1 M mannitol (which is less hyperosmotic than commonly used mannitol) at 4 degrees in Sprague-Dawley (SD) rats. To measure the changes in cerebrovascular permeability, perfusate-containing [14C]-sucrose was infused intra-arterially at different time points following hyperosmotic and hypothermic stress. Cerebrovascular permeability was then measured with the in situ brain perfusion technique. 1.6 M Mannitol produced opening of the BBB but the duration of the opening was less than 30 minutes. Use of 1.1 M Mannitol at 4 degrees indicated the same results. We then investigated the effect of a Na/Ca ion exchange blocker (KB-R7943) in both hyperosmotic and hypothermic BBB opening. KB-R7943 extended BBB opening up to 30 min without affecting the peak level of BBB permeability at 5 minutes. Our findings represent important experimental information regarding pharmacological manipulation of BBB opening. The possibility of prolonging the transient opening of the BBB has major clinical implications.