Metals in our minds: therapeutic implications for neurodegenerative disorders

摘要

Abnormal interactions of copper or iron in the brain with metal-binding proteins (such as amyloid-beta peptide [A(beta)] or neuromelanin) that lead to oxidative stress have emerged as important potential mechanisms in brain ageing and neurodegenerative disorders. Although a controlled study of desferrioxamine in Alzheimer's disease (AD) had some promising results, concerns about toxicity and brain delivery have limited trials of traditional chelators. The therapeutic significance of metal dysregulation in neurodegenerative disorders has remained difficult to test. Clioquinol was identified as a prototype metal-protein-attenuating compound (MPAC). In a blinded and controlled 9 week study of a mouse model of AD. oral clioquinol decreased brain A(beta) by 49% without systemic toxicity. The concentrations of copper and zinc in the brain rose by about 15% in mice treated with clioquinol. Two other studies in mice showed that the raising of brain copper concentrations through diet or genetics could lower amyloid load and increase survival. A recent placebo-controlled trial in 36 patients with AD showed that clioquinol (250-750 mg daily) reduced plasma concentrations of A(beta), raised plasma concentrations of zinc, and-in a subset with moderate dementia-slowed cognitive decline over 24 weeks.