Peripheral phosphodiesterase 4 inhibition produced by 4-[2-(3,4-Bis-difluoromethoxyphenyl)-2-[4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-phenyl]-ethyl]-3-methylpyridine-1-oxide (L-826,141) prevents experimental autoimmune encephalomyelitis.
Administration of phosphodiesterase 4 (PDE4) inhibitors suppresses the pathogenesis associated with experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS). In the present study, we compared the effects of rolipram and 4-[2-(3,4-bis-difluoromethoxyphenyl)-2-[4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-phenyl]-ethyl]-3-methylpyridine-1-oxide (L-826,141), a novel nonbrain penetrant PDE4 inhibitor, on the onset and severity of clinical signs in a chronic, nonrelapsing/remitting model of EAE. Both rolipram (10 mg/kg p.o.) and L-826,141 (3 mg/kg p.o.) reduced the severity of EAE relative to controls, whereas L-826,141 (3 mg/kg p.o.) also delayed disease onset. To assess whether L-826,141 prevented EAE progression after the first signs of clinical onset, rolipram (10 mg/kg p.o.) or L-826,141 (3 or 30 mg/kg p.o.) were administered 24 h after the first signs of EAE were observed. Only L-826,141 at a dose of 30 mg/kg p.o. significantly decreased the clinical severity of EAE compared with vehicle controls. Immunohistochemical detection of the neuronal activity marker Fos confirmed that L-826,141 did not reach concentrations in the central nervous system sufficient to activate central neurons. Lipopolysaccharide-induced tumor necrosis factor-alpha in whole blood and plasma concentrations of L-826,141 revealed that only the 30-mg/kg dose resulted in levels sufficient to produce a near complete inhibition of PDE4 activity in immune cells. Taken together, these results demonstrate that peripheral PDE4 inhibition, produced by L-826,141, prevents the progression of EAE after the first onset of clinical signs, and suggest that similar compounds may have clinical efficacy in the treatment of MS.
Moore
C S
CS
Department of Pharmacology, Faculty of Medicine, Sir Charles Tupper Bldg., 5850 College St., Halifax, NS B3H 1X5, Canada.
Earl
N
N
Frenette
R
R
Styhler
A
A
Mancini
J A
JA
Nicholson
D W
DW
Hebb
A L O
AL
Owens
T
T
Robertson
G S
GS
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors*; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000517:prevention & control*; D005904:Glial Fibrillary Acidic Protein / Q000032:analysis; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D009103:Multiple Sclerosis / Q000188:drug therapy; D010726:Phosphodiesterase Inhibitors / Q000627:therapeutic use*; D016760:Proto-Oncogene Proteins c-fos / Q000032:analysis; D011725:Pyridines / Q000627:therapeutic use*; D020889:Rolipram / Q000627:therapeutic use; D013116:Spinal Cord / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
D005904:Glial Fibrillary Acidic Protein; C459562:L-826,141; D008070:Lipopolysaccharides; D010726:Phosphodiesterase Inhibitors; D016760:Proto-Oncogene Proteins c-fos; D011725:Pyridines; D014409:Tumor Necrosis Factor-alpha; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D020889:Rolipram