Immunomodulatory effects of berenil, a trypanocidal agent

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African trypanososomiasis, caused by several species of the extracellular protozoan parasite belonging to the genus Trypanosoma, is severe and often fatal disease of humans and livestock. Diminazene aceturate (Berenil) is the drug of choice for treatment of African trypanosomiasis in animals. First described in the mid 1950s, a substantial body of data has been generated on various pharmacological aspects of the compound. However, it is not known whether Berenil mediates its anti-parasitic effects exclusively by destroying blood stream forms of the parasite or by combining its trypanocidal activity with immuno-modulatory effects. An additional immuno-modulatory effect seems plausible in view of the fact that certain antimicrobial agents, originally thought to have only anti-microbial effects have now been shown to exert potent immunomodulatory activities. Furthermore, an exclusive trypanolytic activity does not completely explain certain observations in treated animals. For example, parasitemia in cattle treated with Berenil falls sharply to undetectable level within 8 hr post treatment. In contrast, parasites are still detected after 24 hr in blood samples from treated animals that are incubated at 37 oC, strongly suggesting that destruction of parasites is not the only mechanisms of action of the drug. Recently, we found that treatment of infected highly susceptible BALB/c mice with Berenil leads to complete clearance of parasitemia and a concomitant decrease in the production of IFN-gamma and other proinflammatory cytokines including IL-1ß, IL-6, IL-12 and TNF-alpha. We have confirmed that Berenil potently inhibits LPS-induced production of proinflammatory cytokines by macrophages in vitro. The overarching goal of the studies proposed here is to investigate the cellular and molecular mechanisms of anti-inflammatory properties of Berenil in vitro and in vivo. We believe these studies will elucidate the immunomodulatory and anti-inflammatory effects of Berenil at the molecular and cellular levels and could also help explain the mechanisms of cellular toxicity of Berenil. In addition, they will provide potential selective targets for Berenil and other related drugs for the purposes of controlling inflammatory processes.