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 phosphodiesterase type IV (PDE IV) inhibitors, BBB022 and rolipram, in murine and rat models of experimental autoimmune encephalomyelitis (EAE). Based on our data, we propose a mechanism of action which may supplement immunomodulatory effects of PDE IV inhibitors. In particular, PDE inhibitors promote elevation of intracellular cAMP levels, increasing the electrical resistance of endothelial monolayers by stabilizing intercellular junctional complexes. Such an effect on central nervous system (CNS) vascular endothelium has the potential to reduce disease severity in EAE, because both inflammatory cells and humoral factors readily cross a disrupted blood-brain barrier (BBB). In this 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 provide evidence that PDE IV-inhibitors may exert therapeutic effects in EAE by modifying cerebrovascular endothelial permeability, reducing tissue edema as well as entry of inflammatory cells and factors.
Department of Neurosciences, The Lerner Research Institute of the Cleveland Clinic Foundation, OH 44195, USA.
V A
VA
Folcik
T
T
Smith
S
S
O'Bryant
J A
JA
Kawczak
B
B
Zhu
H
H
Sakurai
A
A
Kajiwara
J M
JM
Staddon
A
A
Glabinski
A L
AL
Chernosky
M
M
Tani
J M
JM
Johnson
V K
VK
Tuohy
L L
LL
Rubin
R M
RM
Ransohoff
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors*; D000208:Acute Disease; D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects* / Q000276:immunology; D001929:Brain Edema / Q000188:drug therapy / Q000276:immunology; D002490:Central Nervous System / Q000201:enzymology / Q000276:immunology; D002908:Chronic Disease; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy* / Q000276:immunology; D005260:Female; D051379:Mice; D008815:Mice, Inbred Strains; D009930:Organic Chemicals; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D011760:Pyrrolidinones / Q000494:pharmacology*; D051381:Rats; D011917:Rats, Inbred Lew; D012008:Recurrence; D020889:Rolipram
C119913:BBB022A; D009930:Organic Chemicals; D010726:Phosphodiesterase Inhibitors; D011760:Pyrrolidinones; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D020889:Rolipram