RESUMEN
As part of a program researching the synthesis and immunopharmacological evaluation of novel synthetic compounds, we have described the immune modulatory profile of the new achiral thalidomide analogue LASSBio-468 in the present work. This compound was planned as an N-substituted phthalimide derivate, structurally designed as a hybrid of thalidomide and aryl sulfonamides, which were previously described as tumor necrosis factor-alpha (TNF-alpha) and PDE4 inhibitors. LASSBio-468 was recently demonstrated to inhibit the TNF-alpha production induced by lipopolysaccharide (LPS), in vivo. Here, we investigated whether this compound would affect chronic inflammation processes associated with the production of this pro-inflammatory cytokine. Treatment with LASSBio-468 before a lethal dose injection of LPS in animals greatly inhibited endotoxic shock. This effect seems to be mediated by a specific down regulation of TNF-alpha and nitric oxide production, regulated mainly at the RNA level. In another model, histopathological analysis indicated that this compound also inhibited adjuvant-induced arthritis in rats. Taken together, our data demonstrated a potent anti-inflammatory effect of LASSBio-468, suggesting its use as a potential drug against chronic inflammatory diseases.
Asunto(s)
Artritis Experimental/tratamiento farmacológico , Indoles/farmacología , Óxido Nítrico/sangre , Choque Séptico/tratamiento farmacológico , Talidomida/análogos & derivados , Factor de Necrosis Tumoral alfa/metabolismo , Animales , Antiinflamatorios/farmacología , Artritis Experimental/genética , Artritis Experimental/patología , Expresión Génica/efectos de los fármacos , Isoindoles , Lipopolisacáridos/farmacología , Activación de Linfocitos/efectos de los fármacos , Macrófagos Peritoneales/efectos de los fármacos , Masculino , Ratones , Ratones Endogámicos BALB C , Óxido Nítrico/metabolismo , Pentoxifilina/farmacología , Ratas , Ratas Wistar , Talidomida/farmacología , Factor de Necrosis Tumoral alfa/genética , Vasculitis del Sistema Nervioso Central/tratamiento farmacológico , Vasculitis del Sistema Nervioso Central/patologíaRESUMEN
In this work, we investigated the activity of the platelet activating factor acetyl hydrolase (PAF-AH) in the salivary gland homogenates and saliva of Rhodnius prolixus. PAF-AH activity in the salivary gland homogenates was lower than in the saliva. Preliminary characterization of the enzyme demonstrated that it hydrolyzed the substrate 2-thio-PAF, was detectable just in 1 pair of salivary gland homogenates in 0.5 ml buffer, and was stable under different conditions. PMSF, TPCK, TLCK, pepstatin A and p-BPB all inhibited the PAF-AH activity. Enzyme specific activity in salivary gland homogenates diminished immediately after feeding of 5th-instar larvae, and increased before feeding by adult insects. 2-Thio-PAF induced platelet-aggregation that was inhibited by previous incubation of the substrate with salivary gland homogenates or saliva. The relevance of PAF-AH for providing Rhodnius with a feeding mechanism for facilitating the sucking of a high volume of blood meal in a short period is discussed.