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Research ArticleINFLAMMATION, 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

C. S. Moore, N. Earl, R. Frenette, A. Styhler, J. A. Mancini, D. W. Nicholson, A. L. O. Hebb, T. Owens and G. S. Robertson
Journal of Pharmacology and Experimental Therapeutics October 2006, 319 (1) 63-72; DOI: https://doi.org/10.1124/jpet.106.106096
C. S. Moore
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N. Earl
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R. Frenette
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A. Styhler
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J. A. Mancini
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D. W. Nicholson
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A. L. O. Hebb
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T. Owens
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G. S. Robertson
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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

  • G.S.R. holds a Canadian Institutes of Health Research Research-Based Pharmaceutical Companies Chair.

  • Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.

  • doi:10.1124/jpet.106.106096.

  • 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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Journal of Pharmacology and Experimental Therapeutics: 385 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 385, Issue 3
1 Jun 2023
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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
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Research ArticleINFLAMMATION, 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

C. S. Moore, N. Earl, R. Frenette, A. Styhler, J. A. Mancini, D. W. Nicholson, A. L. O. Hebb, T. Owens and G. S. Robertson
Journal of Pharmacology and Experimental Therapeutics October 1, 2006, 319 (1) 63-72; DOI: https://doi.org/10.1124/jpet.106.106096

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Research ArticleINFLAMMATION, 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

C. S. Moore, N. Earl, R. Frenette, A. Styhler, J. A. Mancini, D. W. Nicholson, A. L. O. Hebb, T. Owens and G. S. Robertson
Journal of Pharmacology and Experimental Therapeutics October 1, 2006, 319 (1) 63-72; DOI: https://doi.org/10.1124/jpet.106.106096
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