Copper-trafficking efficacy of copper-pyruvaldehyde bis(N4-methylthiosemicarbazone) on the macular mouse, an animal model of Menkes disease

Background: Menkes disease (MD) is a disorder of copper transport caused by ATP7A mutations. Although parenteral copper supplements are partly effective in treating MD, the copper level in the brain remains insufficient, whereas copper accumulates in the kidney. We investigated the copper-trafficking efficacy of copper-pyruvaldehyde bis( N 4 -methylthiosemicarbazone) (Cu-PTSM), a lipophilic copper complex, in macular mice, an animal model of MD. Methods: Macular mice were treated with cupric chloride (CuCl 2 ) or Cu-PTSM on postnatal days 4, 10, and 17. At 4 wk of age, the copper levels in major organs and cytochrome oxidase (CO) activity in brain tissue were measured. Hematology, blood biochemistry, and urinary β2-microglobulin (β2-M) secretion were also assessed. Results: The copper levels in the brains of the Cu-PTSM-treated group remained low, but CO activity in the cerebral and cerebellar cortices in the Cu-PTSM-treated group were higher than those in the CuCl 2 -treated group. There were no significant differences in hematological or biochemical findings or in urinary β2-M secretion among the groups. Conclusion: Although the copper-trafficking efficacy of Cu-PTSM was limited, the improved CO activity in the brain suggests that Cu-PTSM delivered copper more effectively to neuronal CO than did CuCl 2 . Reduced renal copper accumulation may be beneficial in prolonged copper supplementation.