References for this review were identified by searches, from Jan 2003-March 2004, of MEDLINE with the terms “Alzheimer's”, “Parkinson's”, or “neurodegeneration” combined with either “metals” or “clioquinol”. References were also identified from relevant articles and through searches of the authors’ files. Abstracts and reports from meetings were included only when they related directly to previously published work. Only papers published in English were reviewed.
Rapid ReviewMetals in our minds: therapeutic implications for neurodegenerative disorders
Section snippets
Metals, amyloid-β (Aβ) peptide, and AD
The basis for MPAC studies in AD is evidence for Aβ precipitation and toxicity owing to abnormal interactions with copper, iron, and zinc.3, 12, 13, 14, 15, 16 Amyloid precursor protein (APP) has copper binding domains that allow it to function as a copper chaperone in the brain.15 There is evidence that copper and iron interact with Aβ to facilitate enzymatic production of hydrogen peroxide, which auto-oxidises Aβ and creates protease resistant soluble and crosslinked Aβ.14, 15, 16 There is
Clioquinol as a prototype MPAC: animal studies
Clioquinol was identified as a prototype MPAC after examining known molecules.2, 22 In post-mortem AD tissue, addition of clioquinol doubled the amount of soluble Aβ released; most Aβ was made soluble with repeated extraction.22 In a 12 week, blind, controlled study of 12-month-old transgenic mice (APP2576 Tg mice, which have AD-type neuropathology), it was determined that clioquinol at a dose of 20 mg/kg/day (but not at a dose of 2 mg/kg/day) significantly decreased sedimentable Aβ with two
Studies of clioquinol in patients with AD
In an initial uncontrolled study, 20 patients with mild to moderate AD received 20 mg or 80 mg of clioquinol daily for 21 days.23 Some cognitive improvements were noted with the higher dose and none had treatment related adverse events. A subsequent 36 week, phase II, placebo-controlled trial in 36 patients with mild to moderate AD was done in patients on stable cholinesterase-inhibitor therapy.24 Clioquinol dose was 125 mg twice daily (weeks 0–12), 250 mg twice daily (weeks 13–24), and 375 mg
Safety issues with clioquinol
Clioquinol was used extensively in the mid 1900s as an antibiotic, but was banned in Japan in 1970 after it was associated with 10 000 cases of SMON.26, 27 This disorder is characterised by subacute onset of visual impairment and sensory and motor disorders in the lower half of the body. Epidemiological studies have linked SMON to clioquinol25 and studies in dogs have replicated clinical features of SMON.28 Mitochondrial toxicity caused by clioquinol-zinc chelate has been proposed as a
MPAC in other neurodegenerative diseases
Studies have described abnormal protein-metal interactions in neurodegenerative diseases—eg, PD, Creutzfeldt-Jakob disease, familial amyotrophic lateral sclerosis, and Freidrich's ataxia (table).1, 5, 6, 7, 8, 9, 10, 11, 32, 33, 34, 35 In many of these disorders it is still unclear if metal dyshomeostasis is a primary causal factor, a secondary contributor, or simply a consequence of the neurodegeneration.
Post mortem and MRI studies in PD have found high concentrations of iron in the substantia
Conclusion
The recent studies of clioquinol in AD and PD provide a new approach to treatment as well as new insights into these disorders. However, whether metal dyshomoeostasis is a primary causal factor of AD or PD, a secondary contributor, or simply a consequence is unknown. Effects of dietary metal supplements on the brain needs further study. Although clioquinol is not the optimal MPAC for therapy, the potential for development of MPAC therapy in neurodegenerative diseases with aberrant metal-protein
Search strategy and selection criteria
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