Transdermal Application of Soluble CuII(atsm) Increases Brain and Spinal Cord Uptake Compared to Gavage with an Insoluble Suspension

Abstract

Cu^II(atsm) is a blood-brain barrier permeant copper(II) compound that is under investigation in human clinical trials for the treatment of neurodegenerative diseases of the central nervous system (CNS). Imaging in humans by positron emission tomography shows the compound accumulates in affected regions of the CNS in patients. Most therapeutic studies to date have utilised oral administration of Cu^II(atsm) in an insoluble form, as either solid tablets or a liquid suspension. However, two pre-clinical studies have demonstrated disease-modifying outcomes following transdermal application of soluble Cu^II(atsm) prepared in dimethyl sulphoxide. Whether differences in the method of administration lead to different degrees of tissue accumulation of the compound has never been examined. Here, we compare the two methods of administration in wild-type mice by assessing changes in tissue concentrations of copper. Both administration methods resulted in elevated copper concentrations in numerous tissues, with the largest increases evident in the liver, brain and spinal cord. In all instances where treatment with Cu^II(atsm) resulted in elevated tissue copper, transdermal application of soluble Cu^II(atsm) led to higher concentrations of copper. In contrast to Cu^II(atsm), an equivalent dose of copper(II) chloride resulted in minimal changes to tissue copper concentrations, regardless of the administration method. Data presented herein provide quantitative insight to transdermal application of soluble Cu^II(atsm) as a potential alternative to oral administration of the compound in an insoluble formulation.

Keywords: copper-ATSM; gavage; neurodegeneration; oral; therapeutic; transdermal.