title: Disease progression in MRL/lpr lupus-prone mice is reduced by NCS 613, a specific cyclic nucleotide phosphodiesterase type 4 (PDE4) inhibitor.
abstract: Systemic lupus erythematosus is a polymorphic and multigenic inflammatory autoimmune disease. Cyclic AMP (cAMP) modulates inflammation and the inhibition of cyclic nucleotide phosphodiesterase type 4 (PDE4), which specifically hydrolyzes cAMP, inhibits TNFα secretion. This study was aimed at investigating the evolution of PDE activity and expression levels during the course of the disease in MRL/lpr lupus-prone mice, and to evaluate in these mice the biological and clinical effects of treatments with pentoxifylline, denbufylline and NCS 613 PDE inhibitors. This study reveals that compared to CBA/J control mice, kidney PDE4 activity of MRL/lpr mice increases with the disease progression. Furthermore, it showed that the most potent and selective PDE4 inhibitor NCS 613 is also the most effective molecule in decreasing proteinuria and increasing survival rate of MRL/lpr mice. NCS 613 is a potent inhibitor, which is more selective for the PDE4C subtype (IC₅₀= 1.4 nM) than the other subtypes (PDE4A, IC₅₀= 44 nM; PDE4B, IC₅₀= 48 nM; and PDE4D, IC₅₀= 14 nM). Interestingly, its affinity for the High Affinity Rolipram Binding Site is relatively low (K(i) = 148 nM) in comparison to rolipram (K(i) = 3 nM). Finally, as also observed using MRL/lpr peripheral blood lymphocytes (PBLs), NCS 613 inhibits basal and LPS-induced TNFα secretion from PBLs of lupus patients, suggesting a therapeutic potential of NCS 613 in systemic lupus. This study reveals that PDE4 represent a potential therapeutic target in lupus disease.
authors.affiliation: CNRS, Biophotonique et Pharmacologie, Faculté de Pharmacie, Université de Strasbourg, Illkirch, France.
authors.forename: Thérèse
authors.initials: T
authors.lastname: Keravis
authors.forename: Fanny
authors.initials: F
authors.lastname: Monneaux
authors.forename: Issaka
authors.initials: I
authors.lastname: Yougbaré
authors.forename: Lucien
authors.initials: L
authors.lastname: Gazi
authors.forename: Jean-Jacques
authors.initials: JJ
authors.lastname: Bourguignon
authors.forename: Sylviane
authors.initials: S
authors.lastname: Muller
authors.forename: Claire
authors.initials: C
authors.lastname: Lugnier
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D000818:Animals; D000242:Cyclic AMP / Q000378:metabolism; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4 / Q000737:chemistry* / Q000378:metabolism*; D018450:Disease Progression; D005260:Female; D006801:Humans; D007527:Isoenzymes; D007668:Kidney / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008180:Lupus Erythematosus, Systemic / Q000188:drug therapy* / Q000201:enzymology / Q000401:mortality*; D051379:Mice; D008808:Mice, Inbred CBA; D019463:Mice, Inbred MRL lpr; D010431:Pentoxifylline / Q000627:therapeutic use; D058988:Phosphodiesterase 4 Inhibitors / Q000627:therapeutic use*; D011507:Proteinuria / Q000188:drug therapy* / Q000209:etiology / Q000401:mortality; D015996:Survival Rate; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014970:Xanthines / Q000627:therapeutic use
chemical_list: C106583:2-trifluoromethyl-9-(2-fluorophenylmethyl)-N-methyladenine; D007527:Isoenzymes; D008070:Lipopolysaccharides; D058988:Phosphodiesterase 4 Inhibitors; D014409:Tumor Necrosis Factor-alpha; D014970:Xanthines; C043898:denbufylline; D000242:Cyclic AMP; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D000225:Adenine; D010431:Pentoxifylline