The curious case of clioquinol
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Use of non-specific chelators (i.e., CQ) that do not interact selectively with the Aβ-metal species exhibit adverse side effects that will likely limit their long term clinical use.
“However, use of non-specific chelators (i.e., CQ) that do not interact selectively with the Aβ–metal species exhibit adverse side effects that will likely limit their long term clinical use.3,28,29,31,44,46–48”
From Bifunctional Compounds for Controlling Metal-Mediated Aggregation of the Aβ<sub>42</sub>Peptide (2012) · cites this paper as [46]
Cites
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Genetic or Pharmacological Iron Chelation Prevents MPTP-Induced Neurotoxicity In Vivo
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Experimental and clinical neurotoxicology
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Experimental and clinical neurotoxicology
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Anticancer Activity of the Antibiotic Clioquinol
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RELATION BETWEEN SUBACUTE MYELO-OPTIC NEUROPATHY (S.M.O.N.) AND CLIOQUINOL: NATIONWIDE SURVEY
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The Anti-neurodegeneration Drug Clioquinol Inhibits the Aging-associated Protein CLK-1
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Epidemiological approach to SMON (subacute myelo-optico-neuropathy).
SHIGEMATSU, I., Yanagawa, H., YAMAMOTO, S.-I., & Nakae, K. (1975) · PubMed · Cited by 4 · see citing works
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Bioinorganic Chemistry of Alzheimer’s Disease
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“5-Chloro-7-iodo-8-hydroxyquinoline (clioquinol; a conventional metal (Cu, Zn) chelator and an ionophore), the discarded indigestion drug (54) that might move trace metals outside the cell where their accumulation may cause neuronal damage, provided some benefit in AD models.”
Jaiser, S. R., & Winston, G. P. (2010) · Journal of Neurology · doi:10.1007/s00415-010-5511-x · Cited by 366 · see citing works
“There is renewed interest in clioquinol as a treatment for Alzheimer’s disease and cancer [5].”
Background8-Hydroxyquinolines in medicinal chemistry: A structural perspective
Oliveri, V., & Vecchio, G. (2016) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2016.05.007 · Cited by 282 · see citing works
Small Molecule Modulators of Copper-Induced Aβ Aggregation
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Bifunctional Compounds for Controlling Metal-Mediated Aggregation of the Aβ<sub>42</sub>Peptide
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“Since that time, others have pointed out that SMON was not seen in other countries where clioquinol was widely used, and have criticized the epidemiological data that led to its banning [4; 8; 9; 10].”
Copper Toxicity Links to Pathogenesis of Alzheimer’s Disease and Therapeutics Approaches
Ijaz, H. W., Wang, W., & Lang, M. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21207660 · Cited by 146 · see citing works
“Much later, followed by the same approach, the first-generation of metal chelator, a lipophilic small molecule clioquinol (5-chloro-7-iodo-8HQ or CQ) was introduced at the end of the 1990s [244,255].”
BackgroundMetal ionophores – An emerging class of anticancer drugs
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“It was first produced in Switzerland in the early part of the last century, and was widely used as an antibiotic for the treatment of diarrhea and skin infection (40).”
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Current therapeutic targets for the treatment of Alzheimer’s disease
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“205 Cahoon L. The curious case of clioquinol. Nat. Med. 15(4), 356–359 (2009). 206 Wang Y, Branicky R, Stepanyan Z et al.”
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“whether the therapeutic efficacy of drugs of this class rests on their chelating properties.([270,274]) The binding affinities of clioquinol and homologues may well be insufficient to dislodge Cu from its ECM binding sites.”
BackgroundRana, M., & Sharma, A. (2019) · Metallomics · doi:10.1039/c8mt00203g · Cited by 80 · see citing works
Biological activity of synthetic ionophores: ion transporters as prospective drugs?
Alfonso, I., & Quesada, R. (2013) · Chemical Science · doi:10.1039/c3sc50882j · Cited by 101 · see citing works
Effects of Clioquinol on Metal-Triggered Amyloid-β Aggregation Revisited
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“However, long-term treatment with clioquinol was reported to be limited by an adverse side effect (41).”
Toward a Rational Design to Regulate β-Amyloid Fibrillation for Alzheimer’s Disease Treatment
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“Clioquinol is known to chelate and redistribute iron [98,99,133–136].”
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“The role of the antiprotozoal metal chelator clioquinol in AD, which has been reported to reduce beta-amyloid plaques, presumably by chelation associated with copper and zinc, is currently in clinical trials as potential for treatment of AD [77, 78].”
BackgroundClioquinol and other hydroxyquinoline derivatives inhibit Aβ(1–42) oligomer assembly
LeVine, H., Ding, Q., Walker, J. A., Voss, S. R., & Augelli‐Szafran, C. E. (2009) · Neuroscience Letters · doi:10.1016/j.neulet.2009.08.002 · Cited by 64 · see citing works
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“Unfortunately, the long-term use of CQ is limited by subacutemyelo-optic neuropathy as an adverse side effect [179, 180].”
BackgroundNew Cyclodextrin‐Bearing 8‐Hydroxyquinoline Ligands as Multifunctional Molecules
Oliveri, V., Puglisi, A., Viale, M., Aiello, C., Sgarlata, C., Vecchio, G., Clarke, J., Milton, J., & Spencer, J. (2013) · Chemistry - A European Journal · doi:10.1002/chem.201300237 · Cited by 53 · see citing works
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“It affected thousands of people who were blinded, paralyzed or confined to wheelchairs for the rest of their lives (Cahoon, 2009).”
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Copper and cuproptosis: new therapeutic approaches for Alzheimer’s disease
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“OH quinoline (Lannfelt et al., 2008) that has been developed as an ion carrier (Bush, 2008; Cahoon, 2009).”
BackgroundAlternative approaches for PET radiotracer development in Alzheimer's disease: imaging beyond plaque
Holland, J. P., Liang, S. H., Rotstein, B. H., Collier, T. L., Stephenson, N. A., Greguric, I. D., & Vasdev, N. (2013) · Journal of Labelled Compounds and Radiopharmaceuticals · doi:10.1002/jlcr.3158 · Cited by 43 · see citing works
Nanomaterials for Modulating the Aggregation of β-Amyloid Peptides
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“However, they have some disadvantages, such as poor permeability of the BBB and limited ability to distinguish toxic metal ions related to Aβ aggregates from those associated with normal biological homeostasis [62,63].”
BackgroundROS responsive mesoporous silica nanoparticles for smart drug delivery: A review
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“However, long-term use of CQ has adverse side effects [78] due to the cytotoxicity of elevated levels of copper-CQ complexes (same as in the case of 8-HQ) [74].”
BackgroundUnusual Cyclodextrin Derivatives as a New Avenue to Modulate Self‐ and Metal‐Induced Aβ Aggregation
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Copper homeostasis and the ubiquitin proteasome system
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Brazilin inhibits the Zn2+-mediated aggregation of amyloid β-protein and alleviates cytotoxicity
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Two macrocyclic polyamines as modulators of metal-mediated Aβ40aggregation
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“More recent studies revealed that SMON might be due to other biologic factors and/or pharmacogenetics primarily linked to the Japanese population (Perez et al., 2019; Cahoon, 2009; Meade, 1975).”
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“[10].”
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“HHV‐6 infection is associated with neuro‐ logical disorders such as febrile seizure, epilepsy, and encephalitis (Yao et al., 2009), while EBV infection has been associated with CNS vasculitis (Kano et al., 2017).”
BackgroundInfluentialRana, M., Pareek, A., Bhardwaj, S., Arya, G., Nimesh, S., Arya, H., Bhatt, T. K., Yaragorla, S., & Sharma, A. K. (2020) · RSC Advances · doi:10.1039/d0ra05172a · Cited by 17 · see citing works
Label-free methods for probing the interaction of clioquinol with amyloid-β
Cheng, X. R., Hung, V. W. S., Scarano, S., Mascini, M., Minunni, M., & Kerman, K. (2012) · Analytical Methods · doi:10.1039/c2ay25123j · Cited by 17 · see citing works
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Cuproptosis: mechanisms and links with Alzheimer’s disease
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“Obviously, it was found that sensory disturbances were profound in clioquinol-deteriorated patients in Japan, reaching 97% of mainly feminine cases [16], which is in line with the present findings of PCA.”
Clioquinol induces autophagy by down-regulation of calreticulin in human neurotypic SH-SY5Y cells
Lv, X., Fan, Z., Cao, F., Liu, W., Huang, Z., & Shi, P. (2022) · Chemico-Biological Interactions · doi:10.1016/j.cbi.2022.110268 · Cited by 9 · see citing works
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“…(Hervella‐Garcés, García‐Gavín, Silvestre‐Salvador, & en representación del Grupo Español de Investigación en Dermatitis de Contacto y Alergia Cutánea GEIDAC, 2016; Hojyo, 1987) and indigestion and diarrhea (Cahoon, 2009), but was withdrawn from the market due to its neurological toxicity.”
BackgroundROS Responsive Silica Nanoparticles for Controlled and Targeted Drug Delivery
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“Clioquinol acts as a mild metal chelator, binding metals like iron, copper and zinc in the body and was used as an antibiotic for treating diarrhea and skin infection [16].”
BackgroundClioquinol increases the expression of interleukin-8 by down-regulating GATA-2 and GATA-3
Katsuyama, M., Ibi, M., Iwata, K., Matsumoto, M., & Yabe‐Nishimura, C. (2018) · NeuroToxicology · doi:10.1016/j.neuro.2018.06.014 · Cited by 8 · see citing works
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Crosstalk between copper, Alzheimer’s disease, and melatonin
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“Another investigation demonstrated that Clioquinol (CQ) functions as a metal chelating agent for zinc, copper, and iron (Cahoon 2009).”
Electrochemical Detection of Interaction Between α‐Synuclein and Clioquinol
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Copper in Brain and Neurodegeneration
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8-Hydroxyquinoline Derivatives as Drug Candidates for the Treatment of Alzheimer's Disease
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Chlamydia Infection’s Role in Neurological Diseases
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Ligands as a Tool to Tune the Toxicity of Cu on Bacteria: from Boosting to Silencing
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Ming, L. (2014) · Patai's chemistry of functional groups · doi:10.1002/9780470682531.pat0602 · Cited by 1 · see citing works
Chlamydia: Possible Mechanisms of the Long Term Complications
Apan, T. Z. (2012) · InTech eBooks · doi:10.5772/31331
“Metal protein attenuating compounds have been shown to decrease beta amyloid plaques in animal models and antiprotozoal metal chelator clioquinol was used for treatment (Finefrock et al., 2003, Cahoon, 2009).”
MethodErratum: Corrigendum: The curious case of clioquinol
Cahoon, L. (2009) · Nature Medicine · doi:10.1038/nm0509-469b
Self-citationBazana, L. C. G., Carvalho, Â. R., da Silva, R. F., García, S. C., Arbo, M. D., Teixeira, M. L., & Fuentefría, A. M. (2026) · Microorganisms · doi:10.3390/microorganisms14081654
“However, in the 1990s, clioquinol was studied again and showed promising results in the treatment of Alzheimer’s disease with controlled doses, without adverse effects [46].”
- Authors
- Cahoon, L.
- Corresponding author
- Cahoon, Lauren
- Venue
- Nature Medicine
- Published
- 2009-04
- Volume
- 15
- Issue
- 4
- Pages
- 356-359
- ISSN
- 1078-8956 (ISSN-L)
- 1546-170X
- OpenAlex
- W2014451016
- Cited by
- 83
- References
- 12
- Citations by year
- 2026: 1 · 2025: 5 · 2024: 3 · 2023: 7 · 2022: 3 · 2021: 4 · 2020: 2 · 2019: 3 · 2018: 6 · 2017: 4 · 2016: 4 · 2015: 6 · 2014: 5 · 2013: 6 · 2012: 8
- FWCI
- 5.07
- Type
- journal article
- Language
- en
- Update notices
- erratum (2009-05-01)
- Open access
- closed
- Locations
- Nature Medicine (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Pharmacology › Cholinesterase and Neurodegenerative Diseases
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- clioquinol, Alzheimer's disease, drug repurposing, drug safety
- MeSH terms
- Alzheimer Disease, Anti-Infective Agents, Local, Blindness, Humans, Clioquinol, Japan, Memory, Memory Disorders, Paralysis, Randomized Controlled Trials as Topic, Neurodegenerative Diseases
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