Abstract
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, Zip4), 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.
Highlights
The identification of acrodermatitis enteropathica (AE) as a distinct disease entity was first made by Danbolt and Closs in 1942, who postulated that AE was a “primary affection of the intestinal tract”(reviewed in [1])
Did not significantly alter the levels of the other metals measured. These in vitro did not significantly alter the levels of the other metals measured. These in vitro zinc zinc ionophore data are consistent with the apparent protective effect of the compound in the AE
Longer-term studies will allow us to assess whether the AE-associated zinc insufficiency translates to CNS deficits that impact/translate to impairments in higher order functions such as learning and memory, or contribute to other metal-associated psychiatric manifestations. These studies demonstrate that zinc diethyl bis(N4-methylthiosemicarbazone) (Zn-DTSM) is a potent zinc ionophore that may have utility in the treatment of zinc deficiency disorders, such as AE
Summary
The identification of acrodermatitis enteropathica (AE) as a distinct disease entity was first made by Danbolt and Closs in 1942, who postulated that AE was a “primary affection of the intestinal tract”(reviewed in [1]). The introduction of AE-associated missense mutations into the ZIP4 gene in mice resulted in decreased cellular uptake of zinc [9] These cumulative discoveries around the pathogenesis of AE, which have been extensively reviewed (e.g., [10]), have led to the long-term treatment for AE being life-long high-dose zinc supplementation [11]. Whilst this approach has been effective, the use of zinc supplementation (in healthy individuals, as well as in those with zinc deficiency disorders such as AE) could lead to a number of adverse effects, such as deficiencies in other key nutrients such as copper [12,13,14,15]. AE patients can be faced with a “juggling act” to maintain nutritional balance and to avoid subsequent clinical manifestations
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