Benznidazole, a drug employed in the treatment of Chagas' disease, down-regulates the synthesis of nitrite and cytokines by murine stimulated macrophages

Benznidazole (BZL) is a nitroheterocyclic drug employed in the chemotherapy of Chagas' disease, a protozoan disease caused by Trypanosoma cruzi. Becau se this parasite mostly replicates in macrophages, we investigated whether BZL was likely to modify the synthesis of macrophage mediators such as nitr ite, tumour necrosis factor-alpha (TNF-alpha), IL-1 beta, IL-6 and IL-10. C ontrol and stimulated murine macrophages (lipopolysaccharide (LPS) and/or i nterferon-gamma (IFN-gamma)) were treated with BZL and measurements were ca rried out in culture supernatants collected 24 h later. Synthesis of nitrit e, IL-6 and IL-10 was maximal upon combined stimulation with LPS + IFN-gamm a, whereas lower amounts of the three mediators were detected when both sti muli were given alone. BZL treatment significantly reduced nitrite, IL-6 an d IL-10 production, to undetectable levels in some cases, particularly IL-6 and IL-10. LPS was the most potent stimulus of IL-1 beta and TNF-alpha pro duction, followed by LPS + IFN-gamma and IFN-gamma in decreasing order. BZL partly inhibited TNF-alpha synthesis, but this effect was smaller than tha t observed for nitrite, IL-6 and IL-10. LPS-induced production of IL-1 beta was also affected by BZL. Semiquantification of gene expression for induci ble nitric oxide synthase (iNOS) showed that BZL completely inhibited iNOS gene induction by IFN-gamma, and resulted in respective inhibitions of 30% and 50% with LPS- and LPS + IFN-gamma-stimulated cells. BZL was not cytotox ic on macrophage cultures, as shown by the lactate dehydrogenase activity. Besides its trypanocidal activity, BZL may also alter the balance between p ro- and anti-inflammatory mediators with important consequences for the cou rse of T. cruzi infection.