Effects of the phosphodiesterase 4 inhibitors SB 207499 and AWD 12-281 on the inflammatory reaction in a model of allergic dermatitis

Eur J Pharmacol. 2002 Jun 20;446(1-3):195-200. doi: 10.1016/s0014-2999(02)01810-1.

Abstract

The inhibitors of the phosphodiesterase 4, SB 207499 (cilomilast, c-4-cyano-4-(3-cyclopentyloxy-4-methoxy-phenyl)-r-L-cyclohexane carboxylic acid) and AWD 12-281 (N-(3,5-dichloropyrid-4-yl)-[1-(4-fluorobenzyl)-5-hydroxy-indole-3-yl]-glyoxylic acid amide) were tested in a model of allergic dermatitis in mice. To obtain an allergic dermatitis, BALB/c mice were sensitized to toluene-2,4-diisocyanate. The allergic reaction was challenged by topical administration of toluene-2,4-diisocyanate onto the mice ears. Before challenge, two groups of mice were treated topically (ear skin) with SB 207499 or AWD 12-281. There was a significant ear swelling in toluene-2,4-diisocyanate-challenged mice ears 4, 8, 16, 24 and 48 h after challenge. SB 207499 and AWD 12-281 inhibited this swelling significantly 8, 16, 24 and 48 h after the challenge. For biochemical parameters and histology, ears were sampled from mice sacrificed 4, 8 and 16 h after the challenge. In homogenized tissue, SB 207499 and AWD 12-281 inhibited significantly the secretion of interleukin 1beta induced by toluene-2,4-diisocyanate 4 and 8 h after challenge. The cell influx (granulocytes) observed in the toluene-2,4-diisocyanate-challenged mice 8 and 16 h after challenge was nearly abolished by AWD 12-281 and SB 204799.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3',5'-Cyclic-AMP Phosphodiesterases / antagonists & inhibitors*
  • Amides / pharmacology*
  • Animals
  • Cyclic Nucleotide Phosphodiesterases, Type 4
  • Cyclohexanecarboxylic Acids / pharmacology*
  • Dermatitis, Allergic Contact / etiology
  • Dermatitis, Allergic Contact / metabolism*
  • Ear / pathology
  • Edema / pathology
  • Immunoglobulin E / metabolism
  • Indoles / pharmacology*
  • Interleukin-1 / metabolism
  • Interleukin-4 / metabolism
  • Mice
  • Mice, Inbred BALB C
  • Nitriles
  • Phosphodiesterase Inhibitors / pharmacology*
  • Skin / metabolism
  • Time Factors
  • Toluene 2,4-Diisocyanate

Substances

  • AWD 12-281
  • Amides
  • Cyclohexanecarboxylic Acids
  • Indoles
  • Interleukin-1
  • Nitriles
  • Phosphodiesterase Inhibitors
  • Toluene 2,4-Diisocyanate
  • Interleukin-4
  • Immunoglobulin E
  • Cilomilast
  • 3',5'-Cyclic-AMP Phosphodiesterases
  • Cyclic Nucleotide Phosphodiesterases, Type 4