Efficacy and gastrointestinal tolerability of ML3403, a selective inhibitor of p38 MAP kinase and CBS-3595, a dual inhibitor of p38 MAP kinase and phosphodiesterase 4 in CFA-induced arthritis in rats.
OBJECTIVE
Mitogen-activated protein kinase (MAPK) p38 inhibitors have entered the clinical phase, although many of them have failed due to high toxicity and lack of efficacy. In the present study we compared the effects of the selective p38 inhibitor ML3403 and the dual p38-PDE4 inhibitor CBS-3595, on inflammatory and nociceptive parameters in a model of polyarthritis in rats.


METHODS
Male Wistar rats (180-200 g) were used for the complete Freund's adjuvant (CFA)-induced arthritis model and they were evaluated at 14-21 days. We also analysed the effects of these pharmacological tools on liver and gastrointestinal toxicity and on cytokine levels.


RESULTS
Repeated CBS-3595 (3 mg/kg) or ML3403 (10 mg/kg) administration produced significant anti-inflammatory actions in the chronic arthritis model induced by CFA. CBS-3595 and ML3403 treatment also markedly reduced the production of the proinflammatory cytokine IL-6 in the paw tissue, whereas it widely increased the levels of the anti-inflammatory cytokine IL-10. Moreover, CBS-3595 produced partial anti-allodynic effects in the CFA model at 4 and 8 days after treatment. Notably, ML3403 and CBS-3595 did not show marked signs of hepatoxicity, as supported by unaltered histological observations in the liver sections. Finally, both compounds were safe in the gastrointestinal tract, according to evaluation of intestinal biopsies.


CONCLUSIONS
CBS-3595 displayed a superior profile regarding its anti-inflammatory effects. Thus p38 MAPK/PDE4 blocking might well constitute a relevant strategy for the treatment of RA.
Applied Pharmacology Laboratory, Faculty of Pharmacy, Pontifícia Universidade Católica do Rio Grande do Sul, Avenida Ipiranga, 6681, Partenon, 90619-900 Porto Alegre, RS, Brazil. fernanda.morrone@pucrs.br or fbmorrone@gmail.com.
Diana A
DA
Koch
Rodrigo B M
RB
Silva
Alessandra H
AH
de Souza
Carlos E
CE
Leite
Natália F
NF
Nicoletti
Maria M
MM
Campos
Stefan
S
Laufer
Fernanda B
FB
Morrone
D000631:Aminopyridines / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D001169:Arthritis, Experimental / Q000139:chemically induced / Q000188:drug therapy*; D001706:Biopsy; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D005620:Freund's Adjuvant / Q000009:adverse effects; D041981:Gastrointestinal Tract / Q000187:drug effects / Q000473:pathology; D007093:Imidazoles / Q000494:pharmacology / Q000627:therapeutic use*; D008099:Liver / Q000187:drug effects / Q000473:pathology; D008297:Male; D058988:Phosphodiesterase 4 Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D011725:Pyridines / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D017208:Rats, Wistar; D016896:Treatment Outcome; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*
C522498:(4-(5-(4-fluorophenyl)-2-methylsulfanyl-3H-imidazol-4-yl)pyridin-2-yl)-(1-phenylethyl)amine; D000631:Aminopyridines; C000588693:CBS-3595; D016207:Cytokines; D007093:Imidazoles; D058988:Phosphodiesterase 4 Inhibitors; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D005620:Freund's Adjuvant; D048051:p38 Mitogen-Activated Protein Kinases
CBS-3595; ML3403; PDE4 modulation; arthritis model; inflammation; p38 inhibitors