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

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 CuII(atsm) in an insoluble form, as either solid tablets or a liquid suspension. However, two pre-clinical studies have demonstrated diseasemodifying outcomes following transdermal application of soluble CuII(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 CuII(atsm) resulted in elevated tissue copper, transdermal application of soluble CuII(atsm) led to higher concentrations of copper. In contrast to CuII(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 CuII(atsm) as a potential alternative to oral administration of the compound in an insoluble formulation.(c) 2022 IBRO. Published by Elsevier Ltd. All rights reserved.

Automated summary

The permeable copper(II) compound is being investigated as a potential treatment for neurodegenerative diseases. The compound accumulates in affected areas of the central nervous system in patients, and studies have shown positive outcomes with transdermal application. This study compared the tissue copper concentrations in mice after oral and transdermal administration, revealing higher concentrations with transdermal application of soluble CuII(atsm). The results suggest that transdermal application could be a viable alternative to oral administration.