Abstract
Background[1,2,4] triazolo [4, 3-a][1,8]naphthyridine derivatives (including NF161 and NF177) were tested for anti-inflammatory, analgesic and antipyretic properties and for their effects on spontaneous locomotor activity in mice and acute gastrolesivity in rats. Both NF161 and NF177 appeared to be anti-inflammatory and analgesic agents without toxic effects or acute gastrolesivity, but NF161 showed stronger anti-inflammatory activity, whereas NF177 was more active as analgesic.MethodsAn EIA kit was used to investigate the ability of NF161 and NF177 to affect prostaglandin E2 (PGE2) and prostacyclin (PGI2) production by human umbilical vascular endothelial cells (HUVEC).The compounds' effects on the production of reactive oxygen species (ROS) by human polymorphonuclear cells (PMNs) were studied in an in vitro cell model, evaluating inhibition of superoxide anion (O2-.) production induced by N-formylmethionyl-leucyl-phenylalanine (FMLP). Their effects on PMN adhesion to HUVEC were also investigated; they were incubated with PMNs and endothelial cells (EC) and challenged by stimuli including Platelet Activating Factor (PAF), FMLP, Phorbol Myristate Acetate (PMA), Tumor Necrosis Factor-α (TNF-α) and Interleukin-1β (IL-1β). Adhesion was quantitated by computerized micro-imaging fluorescence analysis.ResultsNeither compounds modified PGE2 or PGI2 production induced by IL-1α.O2-. production and myeloperoxidase release from PMNs stimulated by FMLP was inhibited in a dose- but not time-dependent manner by both [1,8]naphthyridine derivatives, NF161 being statistically more active than NF177 (P < 0.01).The compounds inhibited adhesion evoked by the pro-inflammatory stimuli PAF, FMLP, TNF-α and IL-1β in a concentration-dependent manner in the 10-6–10-4M range, being more active when PAF was used as stimulus and inactive when cells were challenged by PMA. Both compounds acted both on PMN and HUVEC.ConclusionConsidering the interesting anti-inflammatory effects of these compounds in in vivo models and the absence of acute gastrolesivity, the study improved knowledge of anti-inflammatory properties of NF161 and NF177, also demonstrating their potential in vitro, through inhibition of O2-. production, myeloperoxidase release and PMN adhesion to HUVEC. Negative results on PG production suggest a cyclooxygenase (COX)-independent mechanism.
Highlights
There is currently considerable therapeutic interest in novel anti-inflammatory drugs with mechanisms other than the inhibition of cyclooxigenase activity, typical of nonsteroidal anti-inflammatory drugs (NSAIDs), and devoid of irritant effects on the gastric mucosa and suitable for use in chronic inflammatory diseases
O2-. production and myeloperoxidase release from Polymorphonuclear cell (PMN) stimulated by FMLP was inhibited in a dose- but not timedependent manner by both [1,8]naphthyridine derivatives, NF161 being statistically more active than NF177 (P < 0.01)
The compounds inhibited adhesion evoked by the pro-inflammatory stimuli Platelet Activating Factor (PAF), FMLP, Tumor Necrosis Factor-α (TNF-α) and IL-1β in a concentration-dependent manner in the 10-6–10-4M range, being more active when PAF was used as stimulus and inactive when cells were challenged by Phorbol Myristate Acetate (PMA)
Summary
There is currently considerable therapeutic interest in novel anti-inflammatory drugs with mechanisms other than the inhibition of cyclooxigenase activity, typical of nonsteroidal anti-inflammatory drugs (NSAIDs), and devoid of irritant effects on the gastric mucosa and suitable for use in chronic inflammatory diseases. The authors showed that compound NF161 (Fig. 1) exhibited potent statistically-significant antiinflammatory activity at the carrageenan-induced paw edema assay in rats, and showed interesting anti-aggressive activity (even if only at the highest dose) evaluated in the isolation-induced aggressiveness test in mice; results of a further test at 50 mg/Kg dose to evaluate antinociceptive activity of this compound were not statistically significant. This compound has since been demonstrated to have marked analgesic activity at the acetic-acid-induced writhing test in mice (at 200 and 100 mg/kg) and a complete lack of acute gastrolesivity in rats [17]
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