| Abstrakt: |
In the present study, the protective effect of newly synthesised 2-aminotetralines was investigated in murine models of toxic shock. A few derivatives protected mice against lethality induced by lipopolysaccharide from different bacterial strains and shock induced by staphylococcal enterotoxin B in mice sensitized by D-Galactosamine (D-Galn). Notably, one derivative, S(−)-2-amino-6-fluoro-7-methoxy-1,2,3,4 tetrahydronaphthalene hydrochloride (ST1214), was also effective when administered orally (30 mg kg−1) in a therapeutic regimen. ST1214 markedly inhibited the production of the proinflammatory cytokines, such as tumor necrosis factor- (TNF-), Interleukin-1 (IL-1), Interleukin-12 (IL-12), interferon- (IFN-), as well as the inflammatory mediator nitric oxide (NO), and concurrently enhanced the production of the anti-inflammatory cytokine IL-10. Moreover, ST1214 dose-dependently reduced TNF- production by human peripheral blood mononuclear cells and promonocytic THP-1 cells in vitro.In the latter, ST1214 was found to inhibit lipopolysaccharide-induced TNF- secretion but not cytokine mRNA accumulation. These results suggest that the mechanism of action of ST1214 involves blockade of posttranscriptional events of TNF- production, apparently independent of p38 and ERK kinase activity. These results show beneficial effects of 2-aminotetralines in murine shock models and indicate a distinct counter-regulatory activity in down-regulating proinflammatory cytokine response, and upregulating IL-10. One derivative, i.e., ST1214, can be regarded as a lead compound in the development of novel drugs effective in anti-inflammatory strategies. |
