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

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-kappa B We now proceeded to elucidate the molecular mechanisms by which BZL exerts its inhibitory action on NF-kappa B 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-kappa B 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 beta INF-alpha) PMA or H(2)O(2) Also BZL delayed the activation of p38 MAPK but not that of ERK1/2 and JNK Finally treatment with BZL inhibited I kappa B alpha phosporylation and hence its degradation whereas It did not block I kappa B kinase (IKK) alpha/beta phosphorylation Collectively BZL behaves as a broad range specific inhibitor of NF-kappa B activation Independently of the stimuli tested (C) 2010 Elsevier Ltd All rights reserved