Florey Department of Neuroscience and Mental Health - Research Publications

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Author: Adlard, Paul × Author: Ayton, Scott × Author: Bush, Ashley × Start date: 2019 ×

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    The novel compound PBT434 prevents iron mediated neurodegeneration and alpha-synuclein toxicity in multiple models of Parkinson's disease (vol 5, 53, 2017)
    Finkelstein, DI ; Billings, JL ; Adlard, PA ; Ayton, S ; Sedjahtera, A ; Masters, CL ; Wilkins, S ; Shackleford, DM ; Charman, SA ; Bal, W ; Zawisza, IA ; Kurowska, E ; Gundlach, AL ; Ma, S ; Bush, AI ; Hare, DJ ; Doble, PA ; Crawford, S ; Gautier, ECL ; Parsons, J ; Huggins, P ; Barnham, KJ ; Cherny, RA (BMC, 2021-09-29)
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    Brain Zinc Deficiency Exacerbates Cognitive Decline in the R6/1 Model of Huntington's Disease.
    Ayton, S ; Lei, P ; Appukuttan, AT ; Renoir, T ; Foliaki, S ; Chen, F ; Adlard, PA ; Hannan, AJ ; Bush, AI (Springer Nature, 2020-01)
    There is currently no disease-modifying treatment for Huntington's disease (HD), which is characterized by chorea motor impairment and cognitive decline. The zinc ionophore, PBT2, was previously shown to improve the phenotype of a HD mouse model and reported efficacy in certain cognitive tests in a phase II clinical trial in HD. Here we report that zinc deficiency is a feature of the hippocampus and cortex in the R6/1 mouse model of HD. Low cortical zinc has been shown to induce cognitive impairment, and indeed, dietary restriction of zinc in R6/1 mice was associated with cognitive impairment in the Y-maze, an exacerbated hippocampal long-term potentiation (LTP) deficit and reduction of AMPA receptors (and not other glutamatergic receptors). These data reveal the importance of zinc in maintaining brain function in HD.
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    Zn-DTSM, A Zinc Ionophore with Therapeutic Potential for Acrodermatitis Enteropathica?
    Bray, L ; Volitakis, I ; Ayton, S ; Bush, AI ; Adlard, PA (MDPI, 2019-01)
    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.