A potent and selective p38 inhibitor protects against bone damage in murine collagen-induced arthritis: a comparison with neutralization of mouse TNFalpha
| Autor: | K, Mihara, C, Almansa, R L, Smeets, E E M G, Loomans, J, Dulos, P M F, Vink, M, Rooseboom, H, Kreutzer, F, Cavalcanti, A M, Boots, R L, Nelissen |
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| Rok vydání: | 2008 |
| Předmět: |
Inflammation
Lipopolysaccharides Male Mice Inbred BALB C Pyridines Tumor Necrosis Factor-alpha Prednisolone Blotting Western Anti-Inflammatory Agents Arthritis Experimental p38 Mitogen-Activated Protein Kinases Research Papers Endotoxemia Substrate Specificity Mice Cartilage Mice Inbred DBA Animals Female Enzyme Inhibitors Antibodies Blocking Tomography X-Ray Computed |
| Zdroj: | British journal of pharmacology. 154(1) |
| ISSN: | 0007-1188 |
| Popis: | The p38 kinase regulates the release of proinflammatory cytokines including tumour-necrosis factor-alpha (TNFalpha) and is regarded as a potential therapeutic target in rheumatoid arthritis (RA). Using the novel p38 inhibitor Org 48762-0, we investigated the therapeutic potential of p38 inhibition and compared this to anti-mouse (m)TNFalpha antibody treatment in murine collagen-induced arthritis (CIA).Pharmacological profiles of Org 48762-0 were characterized in kinase assays, cellular assays and in lipopolysaccharide (LPS)-induced inflammation in mice. The effects of Org 48762-0 and of mTNFalpha-neutralization on established arthritis were examined in murine CIA.Org 48762-0 potently inhibited p38alpha kinase with a high degree of kinase selectivity. In cellular assays, Org 48762-0 reduced LPS-induced TNFalpha release. Oral administration of Org 48762-0 in mice showed drug-like pharmacokinetic properties and inhibited LPS-induced cytokine production. These pharmacological characteristics of Org 48762-0 prompted a comparison of therapeutic efficacy with mTNFalpha-neutralization in CIA. Org 48762-0 and anti-mTNFalpha antibody treatment equally inhibited development of arthritis when evaluated macroscopically. Radiological analyses revealed protection against bone damage for both treatments, although statistical difference was reached with Org 48762-0 treatment only. Further, micro-computed tomographical and histopathological analyses confirmed the protective effects of Org 48762-0 on joint damage.Pharmacological targeting of p38 kinase provided good protection against joint tissue damage in CIA. In our experiments, neutralization of mTNFalpha produced less prominent suppression of bone damage. Our data suggest a therapeutic potential for selective and potent p38 inhibitors in RA. |
| Databáze: | OpenAIRE |
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