Effects of DMA (Quinazoline Compound) on inflammatory process / O efeito do DMA (composto quinazolinico) sobre o processo inflamatorio

AUTOR(ES)
DATA DE PUBLICAÇÃO

2008

RESUMO

: Inflammation has a main role in several connective tissue diseases and is an important element of infectious disease physiopathology. Recently it has been linked to obesity, diabetes and cardiovascular diseases. Adenosine, among the various inflammatory process mediators, is a potent autocoid and its bioavailability is limited by catabolism to inosine by adenosine deaminase or by salvage following cellular uptake via adenosine kinase (ADK). Once in extracellular space adenosine interacts with specific cell-surface receptors (A1, A2, A2B, A3) and acts on multiples aspects of the inflammatory process: apoptosis, leukocyte migration, release of proinflammatory cytokines and vascular regulation. At cellular level adenosine acts in a wide-range of pathways, modulating important transcription factors like NF-?B. Based on these premises, adenosine immune regulatory properties and potential in therapeutics have been acknowledged and investigated through the study of specific receptors agonists and compounds able to increase its concentration. The main objective of this study was to evaluate the antiinflammatory properties and mechanisms of DMA, a novel adenosine kinase inhibitor, which increases adenosine tissue concentration. In order to accomplished that, animal models of acute inflammation and cell culture assay were used. DMA was orally effective to reduce neutrophils migration (~55%; p <0,05) and IL-6 concentration (~35%; p <0,005) in the aseptic thioglycollate peritonitis model. DMA significantly inhibited arthritis in an acute arthritis carrageenan model, decreasing articular volume (~30% second hour and ~35% fourth hour, p <0,05), leukocytes on synovial liquid (~50% ; 28,6 x 106 ± 5,2 cells/ml vs. 13,8 x 106 ± 1,7 cells/ml; p <0,05) and pain score (2,62 ± 0,18 vs. 1,53 ± 0,136; p <0 ,05). DMA was also effective in reducing edema in the carrageenan-induced paw edema model (~30% second hour and 36% fourth hour; p <0,05) and pain in the second phase of the "Liking test" induced by formalin (~40% in liking time; p <0,01). In vitro, macrophage expression of TLR4, an important cell receptor in recognizing and processing antigens, was decreased after DMA treatment. The results suggest that DMA also impacts the inflammatory cascade by modulating inflammatory related nuclear transcription. It was demonstrated that DMA was also able to inhibit macrophages and neutrophils, LPS induced NF-?B activation and promote PPAR activation in THP-1 cells. Antiinflammatories are drugs in high demand, but their use is still limited by side-effects. The DMA is a novel, potent non-nucleoside ADK inhibitor, orally effective to improve inflammation in some well characterized animal models and in vitro assays. New studies, based on this data, will be design to further explore the therapeutic use of DMA in inflammatory diseases

ASSUNTO(S)

quinazolines inflamação adenosine inflammation adenosina quinazolinas

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