Benznidazole blocks NF-@kB activation but not AP-1 through inhibition of IKK

Mol Immunol 47(15):7 (2010) PMID 20598748

Previously, we demonstrated that benznidazole (BZL), known for its antiparasitic action on Trypanosoma cruzi, modulates pro-inflammatory cytokines and NO release in macrophages by inhibiting NF-@kB. We now proceeded to elucidate the molecular mechanisms by which BZL exerts its inhibitory action on NF-@kB. We demonstrated that the inhibitory effect of BZL is not extended to other macrophage responses, since it did not inhibit other typical hallmarks of macrophage activation such as phagocytosis, MHC-II molecules expression or production of reactive oxygen species (ROS) by NADPH oxidase. BZL was able to interfere specifically with the activation of NF-@kB pathway without affecting AP-1 activation in RAW 264.7 macrophages, not only in LPS-mediated activation, but also for other stimuli, such as pro-inflammatory cytokines (IL-1@b, TNF-@a), PMA or H"2O"2. Also, BZL delayed the activation of p38 MAPK, but not that of ERK1/2 and JNK. Finally, treatment with BZL inhibited I@kB@a phosporylation and hence its degradation, whereas it did not block I@kB kinase (IKK) @a/@b phosphorylation. Collectively, BZL behaves as a broad range specific inhibitor of NF-@kB activation, independently of the stimuli tested.