The In Vitro and In Vivo Effect of Lipoxygenase Pathway Inhibitors Nordihydroguaiaretic Acid and Its Derivative Tetra--methyl Nordihydroguaiaretic Acid against 544.

This study investigated the contribution of lipoxygenase (LOX) inhibitors, nordihydroguaiaretic acid (NDGA), tetra--methyl nordihydroguaiaretic acid (MN) and zileuton (ZIL), and thromboxane A2 (TXA) inhibitor 4,5-diphenylimidazole (DPI) in the proliferation of infection. None of the compounds affected the uptake of into the macrophages. We determined the effect of neutralizing leukotriene B4 (LTB4) receptor and showed that the uptake of the bacteria was inhibited at 30 min post-infection. MN treatment attenuated intracellular survival of at 2 h post-incubation but it was not observed in the succeeding time points. DPI treatment showed reduced survival of at 24 h post-incubation while blocking LTB4 receptor was observed to have a lower intracellular growth at 48 h post-incubation suggesting different action of the inhibitors in the course of the survival of within the cells. Reduced proliferation of the bacteria in the spleens of mice was observed in animals treated with ZIL or DPI. Increased serum cytokine level of TNF-α and MCP-1 was observed in mice treated with MN or ZIL while a lower IFN-γ level in ZIL-treated mice and a higher IL-12 serum level in DPI-treated mice were observed at 7 d post-infection. At 14 d post-infection, ZIL-treated mice displayed reduced serum level of IL-12 and IL-10. Overall, inhibition of 5-LOX or TXA or a combination therapy promises a potential alternative therapy against infection. Furthermore, strong ligands for LTB4 receptor could also be a good candidate for the control of infection.