Immunomodulatory effects of berenil, a trypanocidal agent

非洲锥虫病是由属于锥虫属的几种胞外原虫引起的，是一种严重的、往往是致命的人畜疾病。乙酸双咪唑酯(贝雷尼)是治疗动物非洲锥虫病的首选药物。在20世纪50年代中期首次被描述，已经产生了关于该化合物的各种药理方面的大量数据。然而，目前尚不清楚贝雷尼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相结合来发挥其抗寄生虫作用。考虑到某些最初被认为只有抗微生物作用的抗菌剂现在被证明具有强大的免疫调节活性，另一种免疫调节作用似乎是可信的。此外，唯一的胰酶溶解活性并不能完全解释在接受治疗的动物身上观察到的某些现象。例如，用贝雷尼治疗的牛的寄生虫血症在治疗后8小时内急剧下降到检测不到的水平。相比之下，在37℃孵化的处理动物的血液样本中，24小时后仍能检测到寄生虫，这有力地表明，摧毁寄生虫并不是该药物唯一的作用机制。最近，我们发现贝雷尼治疗感染高度敏感的BALB/c小鼠后，寄生虫血症完全清除，伴随而来的是干扰素-γ和其他促炎细胞因子的产生减少，包括IL-1？、IL-6、IL-12和肿瘤坏死因子-α。我们已经证实，贝雷尼在体外能有效地抑制内毒素诱导的巨噬细胞产生促炎细胞因子。本研究的主要目的是研究贝雷尼的体内外抗炎作用的细胞和分子机制。我们相信这些研究将从分子和细胞水平阐明贝雷尼的免疫调节和抗炎作用，并有助于解释贝雷尼的细胞毒性机制。此外，它们还将为贝雷尼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.