Immunomodulatory effects of berenil, a trypanocidal agent

Berenil（一种杀锥虫剂）的免疫调节作用

• 批准号: 288314-2009
• 负责人: Uzonna, Jude
• 金额: $ 3.35万
• 依托单位: University of Manitoba
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2011
• 资助国家: 加拿大
• 起止时间: 2011-01-01 至 2012-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=480479
• 关键词: Immunomodulatory; effects; berenil; trypanocidal; agent

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.

非洲锥虫病由属于锥虫属的几种细胞外原生动物寄生虫引起，是人类和牲畜的严重且通常致命的疾病。 Diminazene aceturate (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，关于该化合物的各个药理学方面已经产生了大量数据。然而，尚不清楚 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相结合来介导其抗寄生虫作用。鉴于某些抗菌剂最初被认为仅具有抗微生物作用，现在已被证明具有有效的免疫调节活性，因此额外的免疫调节作用似乎是合理的。此外，独特的锥虫分解活性并不能完全解释治疗动物中的某些观察结果。例如，用 Berenil 治疗的牛体内的寄生虫血症在治疗后 8 小时内急剧下降至不可检测的水平。相比之下，24 小时后，在 37 oC 下孵育的处理动物的血液样本中仍然检测到寄生虫，这强烈表明消灭寄生虫并不是该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性 BALB/c 小鼠可完全清除寄生虫血症，并同时减少 IFN-γ 和其他促炎细胞因子（包括 IL-1ß、IL-6、IL-12 和 TNF-α）的产生。 我们已经证实，Berenil 在体外能有效抑制 LPS 诱导的巨噬细胞产生促炎细胞因子。这里提出的研究的总体目标是研究 Berenil 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，并有助于解释 Berenil 的细胞毒性机制。此外，它们还将为 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。