Immunomodulatory effects of berenil, a trypanocidal agent

非洲锥虫病是由属于锥虫属的几种细胞外原生动物寄生虫引起的，是人类和牲畜的严重且通常致命的疾病。醋氨酰地咪嗪（Berenil）是治疗动物非洲锥虫病的首选药物。首次描述于20世纪50年代中期，已经产生了大量关于该化合物的各种药理学方面的数据。然而，还不知道Berenil是否仅通过破坏寄生虫的血流形式或通过将其杀锥虫活性与免疫调节作用结合来介导其抗寄生虫作用。考虑到某些最初被认为仅具有抗微生物作用的抗菌剂现在已显示出具有强效免疫调节活性，额外的免疫调节作用似乎是合理的。此外，唯一的锥虫溶解活性不能完全解释给药动物中的某些观察结果。例如，用Berenil处理的牛的寄生虫血症在处理后8小时内急剧福尔斯至不可检测的水平。相比之下，在37 ℃下孵育24小时后，在给药动物的血液样品中仍然检测到寄生虫，这强烈表明寄生虫的破坏不是药物的唯一作用机制。最近，我们发现用Berenil治疗感染的高度易感的BALB/c小鼠导致寄生虫血症的完全清除和IFN-γ和其他促炎细胞因子（包括IL-1 β、IL-6、IL-12和TNF-α）的产生的伴随减少。 我们已经证实Berenil在体外有效地抑制LPS诱导的巨噬细胞产生促炎细胞因子。本文提出的研究的总体目标是研究Berenil在体外和体内抗炎特性的细胞和分子机制。我们相信这些研究将在分子和细胞水平上阐明Berenil的免疫调节和抗炎作用，也有助于解释Berenil的细胞毒性机制。此外，它们将为Berenil和其他相关药物提供潜在的选择性靶点，以控制炎症过程。

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.