The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, 30 Royal Parade, Parkville, Victoria 3052, Australia.
Nutrients. 2019 Jan 21;11(1):206. doi: 10.3390/nu11010206.
Acrodermatitis enteropathica (AE) is a rare disease characterised by a failure in intestinal zinc absorption, which results in a host of symptoms that can ultimately lead to death if left untreated. Current clinical treatment involves life-long high-dose zinc supplements, which can introduce complications for overall nutrient balance in the body. Previous studies have therefore explored the pharmacological treatment of AE utilising metal ionophore/transport compounds in an animal model of the disease (conditional knockout (KO) of the zinc transporter, ), with the perspective of finding an alternative to zinc supplementation. In this study we have assessed the utility of a different class of zinc ionophore compound (zinc diethyl bis(N4-methylthiosemicarbazone), Zn-DTSM; Collaborative Medicinal Development, Sausalito, CA, USA) to the one we have previously described (clioquinol), to determine whether it is effective at preventing the stereotypical weight loss present in the animal model of disease. We first utilised an in vitro assay to assess the ionophore capacity of the compound, and then assessed the effect of the compound in three in vivo animal studies (in 1.5-month-old mice at 30 mg/kg/day, and in 5-month old mice at 3 mg/kg/day and 30 mg/kg/day). Our data demonstrate that Zn-DTSM has a pronounced effect on preventing weight loss when administered daily at 30 mg/kg/day; this was apparent in the absence of any added exogenous zinc. This compound had little overall effect on zinc content in various tissues that were assessed, although further characterisation is required to more fully explore the cellular changes underlying the physiological benefit of this compound. These data suggest that Zn-DTSM, or similar compounds, should be further explored as potential therapeutic options for the long-term treatment of AE.
肠病性肢端皮炎（AE）是一种罕见的疾病，其特征是肠道锌吸收失败，导致多种症状，如果不治疗最终可能导致死亡。目前的临床治疗包括终身高剂量锌补充剂，但这会给身体的整体营养平衡带来并发症。因此，以前的研究探索了利用疾病动物模型（锌转运体的条件敲除（KO））中的金属离子载体/转运化合物对 AE 进行药理学治疗的方法，以期找到替代锌补充剂的方法。在这项研究中，我们评估了一种不同类别的锌离子载体化合物（锌二乙基双（N4-甲基硫代半卡巴腙），Zn-DTSM；合作药物开发，加利福尼亚州索萨利托）的效用，与我们之前描述的化合物（氯喹醇）相比，以确定它是否能有效预防疾病动物模型中典型的体重减轻。我们首先利用体外测定来评估该化合物的离子载体能力，然后在三项体内动物研究中评估该化合物的作用（在 1.5 个月大的小鼠中每天 30mg/kg，在 5 个月大的小鼠中每天 3mg/kg 和 30mg/kg）。我们的数据表明，当每天以 30mg/kg 的剂量给药时，Zn-DTSM 对预防体重减轻有显著作用；在没有额外添加外源锌的情况下，这种作用很明显。该化合物对各种评估组织中的锌含量总体影响不大，尽管需要进一步的特征描述来更全面地探索这种化合物生理益处的细胞变化。这些数据表明，Zn-DTSM 或类似化合物应作为 AE 的长期治疗的潜在治疗选择进一步探索。
