Abstract
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-α 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.
Footnotes
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G.S.R. holds a Canadian Institutes of Health Research Research-Based Pharmaceutical Companies Chair.
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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doi:10.1124/jpet.106.106096.
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ABBREVIATIONS: MS, multiple sclerosis; CNS, central nervous system; EAE, experimental autoimmune encephalomyelitis; PDE, phosphodiesterase 4; TNF, tumor necrosis factor; IL, interleukin; IFN, interferon; L-826,141, 2-(3,4-bis-difluoromethoxyphenyl)-2-[4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-phenyl]-ethyl]-3-methylpyridine-1-oxide; ELISA, enzyme-linked immunosorbent assay; MOG, myelin oligodendrocyte glycoprotein; CFA, Complete Freund's adjuvant; PFA, paraformaldehyde; DAPI, 4,6-diamidino-2-phenylindole; GFAP, glial fibrillary acidic protein; ANOVA, analysis of variance; LPS, lipopolysaccharide; GM-CSF, granulocyte macrophage-colony-stimulating factor; PB, phosphate buffer; Ro 20-1724, 4-[(3-butoxy-4-methoxyphenyl)-methyl]-2-imidazolidinone.
- Received April 12, 2006.
- Accepted June 28, 2006.
- The American Society for Pharmacology and Experimental Therapeutics
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