Treatment with BBB022A or rolipram stabilizes the blood-brain barrier in experimental autoimmune encephalomyelitis: an additional mechanism for the therapeutic effect of type IV phosphodiesterase inhibitors

We examined the treatment effects of two structurally distinct phosphodiest erase type IV (PDE IV) inhibitors, BBB022 and rolipram, in murine and rat m odels of experimental autoimmune encephalomyelitis (EAE). Based on our data , we propose a mechanism of action which may supplement immunomodulatory ef fects of PDE IV inhibitors. In particular, PDE inhibitors promote elevation of intracellular cAMP levels, increasing the electrical resistance of endo thelial monolayers by stabilizing intercellular junctional complexes. Such an effect on central nervous system (CNS) vascular endothelium has the pote ntial to reduce disease severity in EAE, because both inflammatory cells an d humoral factors readily cross a disrupted blood-brain barrier (BBB), In t his report, we demonstrate the capacity of BBB022 and rolipram to decrease clinical severity of EAE. further, PDE IV inhibitors significantly reduced BBB permeability in the spinal cords of mice with EAE. These results provid e evidence that PDE IV-inhibitors may exert therapeutic effects in EAE by m odifying cerebrovascular endothelial permeability, reducing tissue edema as well as entry of inflammatory cells and factors. (C) 1999 Elsevier Science B.V. All rights reserved.