Pharmacological treatment of brain copper deficiency — The Association Specialists
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Pharmacological treatment of brain copper deficiency (21781)

Anne A Li 1 , Benjamin G Trist 1 , Tzongtyng Hung 2 , Michael P Gotsbacher 3 , Carl Power 2 , Rachel Codd 3 , Kay L Double 1
  1. Brain and Mind Centre and School of Medical Sciences (Neuroscience), , The University of Sydney, Sydney, New South Wales, Australia
  2. Biological Resources Imaging Lab & Biospecimen Services Mark Wainwright Analytical Centre, Lowy Cancer Research Centre University of New South Wales Sydney, Sydney, New South Wales, Australia
  3. Molecular Biomedicine Research Theme, School of Medical Sciences, Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia

Maintaining physiological levels of copper is crucial for cellular function. Imbalances in cellular copper levels lead to a range of disorders, including rare life-threatening genetic diseases such as Menkes disease and Wilson’s disease, and common neurogenerative disorders, such as Parkinson disease (PD) and amyotrophic lateral sclerosis (ALS). Copper dyshomeostasis represents an early change in PD and ALS, with restoration of physiological copper levels in the central nervous system (CNS) proposed to slow disease progression. The copper-containing ionophore diacetylbis(N(4)-methylthiosemicarbazonato)copper(II) (CuATSM) delivers copper to the CNS and may restore physiological brain copper levels in these, and other, disorders characterised by CNS copper deficiency. However, the dosage and treatment frequency required to achieve CNS copper restoration using CuATSM is unknown. We employed copper-deficient Ctr1+/- mice to model brain copper deficiency and orally treated these animals with 8 mg/kg of CuATSM for either 10, 15 or 21 days. Treatments were performed daily, or 4 days per week, using micropipette-guided drug administration. Copper levels in the cerebellum, cortex, brainstem, deep brain nuclein, serum, muscle, and liver of CuATSM-treated Ctr1+/- mice were compared with untreated Ctr1+/- mice and wild-type C57BL6 mice. We confirmed untreated Ctr1+/- mice have significantly lower levels of copper compared to wild-type C57BL6 mice in all CNS regions studied. Twenty-one days of 8 mg/kg daily CuATSM treatment restored Ctr1+/- mice copper levels in all CNS regions studied to equivalent levels observed in wild-type mice. Data from this study could inform the design of copper supplementation in preclinical research and clinical trials.