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In addition to being an antimicrobial, clioquinol is a copper-zinc (Cu-Zn) chelator. Recent understanding of the metallobiology of Alzheimer’s disease (AD) has led to renewed interest in clioquinol. Knowledge regarding metal-ion metabolism in the brain has suggested that Aβ precipitation and toxicity in AD is caused by abnormal interaction with metal ions like Cu and Zn.1 Cu and Zn are found at high levels in neocortical regions prone to AD abnormality. Clioquinol has been shown to increase solubilisation of Aβ in the AD plaque from postmortem human brain tissue and to reduce brain Aβ deposition in a transgenic mouse model of AD.2 These bench findings led to a pilot clinical trial of clioquinol in AD that showed the drug to be well tolerated.3 Plasma Aβ42 concentrations decreased in the clioquinol group, plasma Zn concentrations increased, and there was no effect on plasma Cu. The authors felt that metal protein attenuating compound drugs like clioquinol are not gross tissue chelators, but facilitate dissociation of Cu and Zn from the lowest affinity metal binding sites on Aβ. Alternatively, the clioquinol dose might have been too low to have an impact on serum Cu concentrations.
Subacute myelo-optico-neuropathy (SMON) is characterised by paraparesis, sensory deficits, and visual impairment. The pathological findings include symmetrical demyelination of the lateral and posterior columns of the spinal cord with optic nerve and peripheral nerve involvement. Extensive epidemiological studies in Japan confirmed that SMON was attributable to ingestion of the antibacterial clioquinol. There were nearly 10 000 cases of SMON in Japan by the end of 1970. This led to banning of clioquinol in 1970. Subsequently new cases of SMON disappeared.
Before clioquinol can be studied on a large scale basis as a treatment for AD, its relation to SMON must be resolved. The mechanism of clioquinol induced SMON was never definitively established. Hypotheses include mitochondrial toxicity of the clioquinol-Zn chelate and vitamin B12 deficiency. We propose a mechanism in which Cu is the mediator. Cu deficiency myelopathy bears striking similarities to the subacute combined degeneration seen in vitamin B12 deficiency4 and to SMON. Optic neuritis has been reported in association with Cu deficiency.5 Cu deficiency in ruminants is known to cause an ataxic myelopathy characterised by demyelination of the spinal cord white matter. We believe that a plausible mechanism of SMON is clioquinol induced Cu deficiency. The re-emergence of interest in clioquinol makes testing this hypothesis in available animal models an important issue.
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