Clinical analysis of longstanding subacute myelo-optico-neuropathy: sequelae of clioquinol at 32 years after its ban

Konagaya, Masaaki; Matsumoto, Akihisa; Takase, Sadao; Mizutani, Tetsuya; Sobue, Gen; Konishi, Tetsuro; Hayabara, Toshiyuki; Iwashita, Hiroshi; Ujihira, Takatoshi; Miyata, Kazuaki; Matsuoka, Yukihiko

doi:10.1016/j.jns.2003.11.007

Cited by 66 publications

(55 citation statements)

References 9 publications

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“…Our imaging experiments using Fura-2, which binds Zn 2ϩ with a 100-fold higher affinity than Ca 2ϩ , revealed that ZnPy stimulates TRPA1-containing neurons as soon as there is a detectable but minimal Zn 2ϩ -mediated increase in the Fura-2 ratio in adjacent cells lacking TRPA1. This means that ZnPy activates TRPA1 in neurons at cellular concentrations of Zn 2ϩ below the K D of Fura-2 for Zn 2ϩ [3 nM; (23) A clinical analysis of over 1,000 patients with CQ-induced SMON found that among the most common symptoms of this syndrome were sensory disturbances, including hypersensitivities as well as loss of sensitivities and dysesthesias (1). The neurological basis for these chronic symptoms is thought to involve damage and alterations to various types of neurons in the sensory pathways including those located within the dorsal column of the spinal cord.…”

Section: Discussionmentioning

confidence: 99%

“…Thirty years after the ban of oral CQ, 40% of patients with SMON are unable to walk independently and approximately 7% suffer from visual impairment. The most common complaints, however, have been different forms of sensory impairments, such as tactile hypo-and hypersensitivity (almost 90% of patients) and dysesthesias (97%) (1). Notably, almost 50% of patients experience pain and 40% have cold sensitivity.…”

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confidence: 99%

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Clioquinol and pyrithione activate TRPA1 by increasing intracellular Zn ²⁺

Andersson

Gentry²,

Moss³

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

123

109

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The antifungal and amoebicidal drug clioquinol (CQ) was withdrawn from the market when it was linked to an epidemic of subacute myelo-optico-neuropathy (SMON). Clioquinol exerts its anti-parasitic actions by acting as a Cu/Zn chelator and ionophore. Here we show that local injections of CQ produce mechanical hyperalgesia and cold hypersensitivity through a mechanism involving TRPA1 in mice. We also show that CQ activates TRPA1 in a Zn 2؉ pain ͉ sensory neurons ͉ TRP channels ͉ zinc T he antifungal and amoebicidal drug clioquinol (CQ) was once widely used to treat gastrointestinal disorders, but was withdrawn from oral preparations when CQ was linked to an epidemic of subacute myelo-optico-neuropathy (SMON) in Japanese patients. Patients with SMON suffer from sensory and motor disorders and visual impairment. Thirty years after the ban of oral CQ, 40% of patients with SMON are unable to walk independently and approximately 7% suffer from visual impairment. The most common complaints, however, have been different forms of sensory impairments, such as tactile hypo-and hypersensitivity (almost 90% of patients) and dysesthesias (97%) (1). Notably, almost 50% of patients experience pain and 40% have cold sensitivity. CQ also has acute sensory effects, and studies on isolated nociceptive fibers in dogs demonstrated that CQ recruited normally quiescent fibers to become sensitive to hyperosmotic stimuli and cold (2), suggesting a direct effect on sensory nerves.CQ exerts its anti-parasitic actions by acting as a moderate affinity Cu/Zn chelator and ionophore. The ionophore activity of CQ contributes to its neurotoxicity (3, 4), but also makes it a useful drug for the treatment of acrodermatitis enteropathica, a rare genetic disorder characterized by insufficient Zn 2ϩ uptake (5, 6). More recently CQ has been shown to reduce Cu/Zn deposits and beta-amyloid accumulation in transgenic mouse models of Alzheimer's disease (7,8), findings that have led to clinical trials of CQ in Alzheimer's patients (9, 10).TRPA1 is expressed in a subpopulation of dorsal root ganglion (DRG) neurons, where it acts as a sensory receptor for environmental irritants and both oxidation and thiol-reactive compounds, some of which are produced endogenously during oxidative stress (11-15). Furthermore, TRPA1 can be activated by increasing the osmolarity of the extracellular solution (16).Transgenic mice lacking TRPA1 have a reduced sensitivity to cold stimuli and punctate mechanical stimulation (17), in addition to a reduced chemical sensitivity to irritants and oxidants (11,12,17,18). The similarity between the modalities affected by CQ in nociceptive fibers (increased sensitivity to cold stimulation and hyperosmotic solutions) and the behavioral deficits of mice lacking TRPA1 (reduced sensitivity to painful cold and mechanical stimuli) led us to examine whether CQ can induce pain behavior acutely in mice through the activation of TRPA1. ResultsPronociceptive Effects of Clioquinol. Tactile and cold hypersensitivity are very common symptoms in pati...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Clioquinol and pyrithione activate TRPA1 by increasing intracellular Zn ²⁺

Andersson

Gentry²,

Moss³

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

123

109

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“…The physiopathology mechanism is unknown but clioquinol is a copper or zinc chelator and this has led to the speculation that clioquinol-induced neurotoxicity may be a consequence of copper deficiency. 1,26,[66][67][68] Lathyrism (India, Bangladesh, and Ethiopia) and Konzo (Africa)…”

Section: Treatment or Prognosismentioning

confidence: 99%

Toxic and Metabolic Myelopathies

Ramalho

Nunes

Rocha

et al. 2016

Seminars in Ultrasound, CT and MRI

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Myelopathy describes any neurologic deficit related to the spinal cord. It is most commonly caused by its compression by neoplasms, degenerative disc disease, trauma, or infection. Less common causes of myelopathy include spinal cord tumors, infection, inflammatory, neurodegenerative, vascular, toxic, and metabolic disorders. Conditions affecting the spinal cord must be recognized as early as possible to prevent progression that may lead to permanent disability. Biopsy is rarely performed, thus the diagnosis and management rely on patient's history, physical examination, laboratory results, and imaging findings. Here we review the clinical presentations, pathophysiological mechanisms, and magnetic resonance imaging findings of myelopathies related to metabolic or toxic etiologies. Semin Ultrasound CT MRI 37:448-465 C 2016 Elsevier Inc. All rights reserved.

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“…[3][4][5] In Japan, there are still more than 2500 SMON patients suffering from severe dysesthesia/paresthesia and ataxic paraplegia. 6 Many autopsy case reports confirmed that the characteristic pathological finding of SMON was a 'dying back neuropathy' in the upper cervical gracile fasciculus (the axon terminals of dorsal root neurons) and the lateral funiculus (the long peripheral terminals of the pyramidal tract). In SMON patients who died at an early stage of the disease, active gliosis and axonal degeneration were detected in the gracile fasciculus (Goll fasciculus), and both the lateral funiculus and dorsal root ganglion were also severely affected.…”

Section: Introductionmentioning

confidence: 99%

Cervical MRI of subacute myelo-optico-neuropathy

et al. 2010

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Study design: Case study. Objectives: Subacute myelo-optico-neuropathy (SMON) is a severe neuro-degenerative disorder caused by poisoning due to over-dose and prolonged oral administration of clioquinol; this disorder was more frequent during [1957][1958][1959][1960][1961][1962][1963][1964][1965][1966][1967][1968][1969][1970]. It is characterized by axonal degeneration and gliosis in the cervical gracile fasciculus. Recently, copper-deficient myelo-neuropathies presenting similar symptoms (that is, painful dysesthesia/paresthesia in the lower limbs, ataxia, spastic paraplegia, autonomic disorders and visual impairment) were reported. Magnetic resonance imaging (MRI) of these patients detected T2-weighted hyperintensities in the cervical spinal cord. An unbalanced zinc-copper metabolism was suggested as one of the candidate pathogenesis of clioquinol toxicity because of its metal-chelating ability. The aim of this study was to present MRI findings of old SMON patients and to compare them with those of current copper-deficient myelo-neuropathies. Setting: Japan. Methods: We conducted and analyzed cervical and brain MRIs of seven old SMON patients who contracted the disorder during the 1960s. Serum iron, magnesium, copper, zinc and ceruloplasmin levels were also measured. Results: Cervical T2-weighted MRIs showed mild volume loss and faint hyperintensities in the dorsal columns, which might reflect residual gliosis. Brain fast fluid-attenuated inversion-recovery images and tractography were normal. Current levels of serum copper and zinc were within almost normal ranges. Conclusion: Although fainter, the abnormal T2 MRI signals we observed were similar to and occurred in the same locations as those reported in copper-deficient myelo-neuropathy patients. We suggest that these findings are useful to study the mechanism of clioquinol toxicity before using it to treat neurodegenerative diseases such as Alzheimer's disease.

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Clinical analysis of longstanding subacute myelo-optico-neuropathy: sequelae of clioquinol at 32 years after its ban

Cited by 66 publications

References 9 publications

Clioquinol and pyrithione activate TRPA1 by increasing intracellular Zn ²⁺

Clioquinol and pyrithione activate TRPA1 by increasing intracellular Zn ²⁺

Toxic and Metabolic Myelopathies

Cervical MRI of subacute myelo-optico-neuropathy

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Clinical analysis of longstanding subacute myelo-optico-neuropathy: sequelae of clioquinol at 32 years after its ban

Cited by 66 publications

References 9 publications

Clioquinol and pyrithione activate TRPA1 by increasing intracellular Zn 2+

Clioquinol and pyrithione activate TRPA1 by increasing intracellular Zn 2+

Toxic and Metabolic Myelopathies

Cervical MRI of subacute myelo-optico-neuropathy

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Clioquinol and pyrithione activate TRPA1 by increasing intracellular Zn ²⁺

Clioquinol and pyrithione activate TRPA1 by increasing intracellular Zn ²⁺