The aggrecanses and matrix metalloproteinases are thought to mediate the degradation of the structural cartilGe in osteoarthritis. Cytokines also play an r Important in the implementation of the main symptoms Me the degenerative process of osteoarthritis pain. Inflammatory cytokines such as IL-1  And TNF It has been shown to modulate pain responses in animal models and may be important in the initiation LY2608204 and maintenance of neuropathic pain. Pretreatment of the rats prior to ligation of the spinal nerves with etanercept anti-TNF or inhibition of cytokines by the p38 inhibitor SB 203580 showed Induces similar degrees of inhibition of mechanical allodynia. SB 203580 has also been shown to reduce IL-1-induced thermal hyperalgesia in rats when administered intrathecally. These data suggest that the inhibition of cytokines may be useful for the treatment of pain in osteoarthritis.
Monoclonal anti-TNF therapies such as infliximab and adalimumab, etanercept TNF receptor fusion protein and the L Soluble fraction of IL 1 receptor anakinra proved for the treatment AT7519 of a number of inflammatory diseases such as arthritis effective arthritis and inflammatory bowel disease. However, these biological cytokine inhibitors have not extensively evaluated in clinical studies of osteoarthritis through a potentially bad leverage ratio and the fact that these drugs are very expensive and must be administered parenterally. A fa Approach is the inhibition of cytokines with inhibitors with low molecular weight, orally active pathways that block cytokines such as p38 MAPK pathway. MAPKs function as a series of modules to start Ing through MAPK kinase kinase MAPK kinases that phosphorylate MAP kinases that phosphorylate After all,.
There are 3 families extracellular MAPK kinases Re-regulated protein, C June NH2 terminal kinase and p38. The p38 family consists of four members: ? ?? ? ?? e ? ?? ? ?w hich are 75% homologous and has further away. P38 cytokine can by various mechanisms such as direct phosphorylation of transcription factors such as AP-1, or the stabilization and increased FITTINGS translation of mRNAs, upregulate the 3 ‘untranslated region AU-rich elements binding protein phosphorylation. Small molecule inhibitors of p38 have been shown to reduce the synthesis of inflammatory cytokines and MMPs. SB 203580 and VX 745 are both potent inhibitors of p38b ut not The specificity A number of common inhibitors of p38 was recently detailed in terms of large sheets of e kinases described.
SB 203580 has a good selectivity t For p38 snail majority of kinases in a panel of over 300 kinases JNK MAPK inhibit some, but not like 3, with an IC50 of approx Hr 100 nM. VX 745 is more accurate, but inhibit certain tyrosine kinases with IC50 10 100-h time ago Than for p38. Many p38 inhibitors evaluated in animal models of rheumatoid arthritis With little work has been done in experimental models of osteoarthritis. One study showed a significant reduction of cartilage and osteophyte formation in rabbits treated resection of the anterior cruciate ligament with the MEK 1/2 inhibitor PD 198306th The present study describes the effect of two well-known p38 inhibitors on the breakdown of cartilage in the model iodoacetate Gelenkverschlei and inhibition of hyperalgesia model Hargraeves.