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INFLAMMATION, IMMUNOPHARMACOLOGY, AND ASTHMA

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

Departments of Pharmacology (C.S.M., N.E., A.L.O.H., G.S.R.) and Psychiatry (G.S.R.), Faculty of Medicine, Dalhousie University, Halifax, Nova Scotia, Canada; Departments of Biology and Medicinal Chemistry, Merck Frosst Centre for Therapeutic Research, Pointe Claire-Dorval, Quebec, Canada (R.F., A.S., J.A.M., D.W.N.); and Neuroimmunology Unit, Montreal Neurological Institute, Montreal, Quebec, Canada (T.O.)

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- 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.

Address correspondence to: Dr. George S. Robertson, Departments of Psychiatry and Pharmacology, Faculty of Medicine, Sir Charles Tupper Bldg., 5850 College St., Halifax, NS B3H 1X5, Canada. E-mail: george.robertson{at}dal.ca