Subacute Myelo-optic Neuropathy Research Articles

Toward the complete understanding of the pathogenic mechanism of clioquinol-induced subacute myelo-optic neuropathy (SMON)

Clioquinol was extensively used as an amebicide to treat indigestion and diarrhea in the mid-1900s. However, it was withdrawn from the market in Japan because its use was epidemiologically linked to an increase in the incidence of subacute myelo-optic neuropathy (SMON). SMON is characterized by the subacute onset of sensory and motor disturbances in the lower extremities with occasional visual impairments, which are preceded by abdominal symptoms. Although pathological studies demonstrated axonopathy of the spinal cord and optic nerves, the underlying mechanisms of clioquinol toxicity have not been elucidated in detail. We previously performed a global analysis of human neuroblastoma cells using DNA chips and demonstrated that clioquinol induced 1) DNA double-strand breaks and subsequent activation of ATM/p53 signaling; 2) the expression of VGF, the precursor of neuropeptides involved in pain reactions, by inducing c-Fos; 3) the expression of interleukin-8, which is reported to be involved in intestinal inflammation, optic neuropathy, and neuropathic pain, by down-regulating GATA-2 and GATA-3. We also demonstrated that clioquinol induced zinc influx and oxidation of the copper chaperone ATOX1, leading to the impairment of the functional maturation of a copper-dependent enzyme dopamine-β-hydroxylase and the inhibition of noradrenaline biosynthesis. Thus, clioquinol-induced neurotoxicity in SMON seems to be mediated by multiple pathways.

A historical analysis of the policy on intractable diseases in Japan and its peculiarity

This article examines the history of the policy concerning a class of diseases called intractable diseases in Japan with a particular focus on the roles of patient support groups in firstly legitimizing the grouping of such diseases and then shaping the nature of the support that the Japanese Ministry of Health and Welfare provided to the patients and their families affected by them. The Ministry started its policy on intractable diseases in 1972, predating the enactment of the 1983 Orphan Drug Act in the United States, which is known to be one of the most important events for the international rare diseases community. This policy decision was triggered by the emergence of subacute myelo-optic neuropathy (SMON) as a social problem in the country in the late 1960s. The Ministry first made its support available to patients with this particular disease and, as a result of a series of actions from patient support groups and their medical and political supporters, the same support was made available to those considered to be in similarly difficult circumstances. The way in which the support was arranged, however, turned out to be structurally divisive, inviting the patient groups to negotiate with the national and local governments separately depending on subject matters, and for about three decades since the start of the policy, they struggled to present their unified voice in the country. The governmental support for intractable diseases was finally revised in the mid-2000s, but as this article demonstrates, that became possible only after the patient groups came to realize the need of presenting a unified voice in their effort to improve the lives of those affected.

NQO1 protects against clioquinol toxicity.

Clioquinol (CQ) was widely used as oral antibiotic before being taken off the market in many countries in 1970, after it was linked to subacute myelo-optic neuropathy (SMON) in Japan, leading to vision loss with many patients left wheelchair-bound. The common pathology of CQ-associated SMON was reproduced in animals but none of the proposed modes of toxicity explained the restriction of CQ-induced SMON to Japan. Given a re-emergence of CQ and related analogues as neuroprotectants, it is crucial to understand the underlying mechanism of CQ-induced toxicity to prevent any potential CQ-associated risks to future patients. A small molecule screen to find drugs that induce mitochondrial dysfunction in vitro identified CQ and the structurally related 8-hydroxyquinoline (8-OHQ). Their mitochondrial liability, pro-oxidative and cytotoxic activity was subsequently confirmed in some cell lines but surprisingly not in others. Subsequent studies in isogenic cell lines demonstrated that the antioxidant protein NQO1 is differentially expressed in the cell lines tested and potently protects against CQ toxicity. CQ-induced reduction of cellular ATP levels, increased lipid peroxidation and elevated cell death was also attenuated by antioxidants, implicating oxidative stress as the core mechanism of CQ-induced toxicity. These in-vitro findings were replicated in zebrafish. Visual acuity in zebrafish larvae that do not express NQO1, was reduced by CQ in a dose-dependent manner, while CQ did not affect visual function in the adult zebrafish that express NQO1. Similarly, pharmacological inhibition of NQO1 activity resulted in CQ-induced oxidative stress in the retina and severe acute systemic toxicity in the adult fish. Given the much higher prevalence of the inactivating C609T NQO1 polymorphism in the Japanese population compared to the European population, the results of this study could for the first time indicate how the geographic restriction of SMON cases to Japan could be explained. Importantly, if CQ or its derivatives are to be used safely for the treatment of neurodegenerative diseases, it seems imperative that NQO1 levels and activity of prospective patients should be ascertained.

Toward the complete understanding of the pathogenic mechanism of clioquinol-induced subacute myelo-optic neuropathy (SMON)

Toward the complete understanding of the pathogenic mechanism of clioquinol-induced subacute myelo-optic neuropathy (SMON)

Clioquinol inhibits dopamine-β-hydroxylase secretion and noradrenaline synthesis by affecting the redox status of the copper chaperone ATOX1

Clioquinol, a chelator and ionophore of copper/zinc, was extensively used as an amebicide to treat indigestion and diarrhea in the mid-1900s. However, it was withdrawn from the market in Japan because its use was epidemiologically linked to an increase in the incidence of subacute myelo-optic neuropathy (SMON). Yet, the pathogenesis of SMON has not been fully elucidated. A reporter assay revealed that clioquinol activated metal response element-dependent transcription in human neuroblastoma SH-SY5Y cells. Clioquinol significantly increased the cellular level of zinc within 1 h, possibly due to its ionophore effects. On the other hand, clioquinol significantly increased the cellular level of copper within 24 h. Clioquinol induced the oxidation of the copper chaperone antioxidant 1 (ATOX1), suggesting its inactivation and inhibition of copper transport. The secretion of dopamine-β-hydroxylase (DBH) and lysyl oxidase, both of which are copper-dependent enzymes, was inhibited by clioquinol, along with decreased noradrenaline levels. In fact, disruption of the ATOX1 gene suppressed the secretion of DBH. Taken together, the disturbance of cellular copper transport by the inactivation of ATOX1 may be one of the mechanisms involved in clioquinol-induced neurotoxicity in SMON.

Clioquinol inhibits dopamine-β-hydroxylase secretion and noradrenaline synthesis by affecting the redox status of ATOX1 and copper transport in human neuroblastoma SH-SY5Y cells.

Clioquinol (5-chloro-7-indo-8-quinolinol), a chelator and ionophore of copper/zinc, was extensively used as an amebicide to treat indigestion and diarrhea in the mid-1900s. However, it was withdrawn from the market in Japan because its use was epidemiologically linked to an increase in the incidence of subacute myelo-optic neuropathy (SMON). SMON is characterized by the subacute onset of sensory and motor disturbances in the lower extremities with occasional visual impairments, which are preceded by abdominal symptoms. Although pathological studies demonstrated axonopathy of the spinal cord and optic nerves, the underlying mechanisms of clioquinol toxicity have not been elucidated in detail. In the present study, a reporter assay revealed that clioquinol (20-50µM) activated metal response element-dependent transcription in human neuroblastoma SH-SY5Y cells. Clioquinol significantly increased the cellular level of zinc within 1h, suggesting zinc influx due to its ionophore effects. On the other hand, clioquinol (20-50µM) significantly increased the cellular level of copper within 24h. Clioquinol (50µM) induced the oxidation of the copper chaperone antioxidant 1 (ATOX1), suggesting its inactivation and inhibition of copper transport. The secretion of dopamine-β-hydroxylase (DBH) and lysyl oxidase, both of which are copper-dependent enzymes, was altered by clioquinol (20-50µM). Noradrenaline levels were reduced by clioquinol (20-50µM). Disruption of the ATOX1 gene suppressed the secretion of DBH. This study suggested that the disturbance of cellular copper transport by the inactivation of ATOX1 is one of the mechanisms involved in clioquinol-induced neurotoxicity in SMON.

Clioquinol changes the expression profiles and redox states of proteins involved in copper/zinc homeostasis

Clioquinol, extensively used as an amebicide to treat indigestion and diarrhea in the mid-1900s, was withdrawn from the market due to an increase in the incidence of subacute myelo-optic neuropathy (SMON). Yet, the pathogenesis of SMON has not been fully elucidated. Since clioquinol is known as a chelator and ionophore of copper and zinc ions, we focused on proteins involved in homeostasis of these metal ions. A global analysis on human neuroblastoma cells demonstrated that among 4 isoforms of metallothionein (MT), a family of metal-binding proteins, 7 subclasses of MT-1 and MT-2A were remarkably up-regulated by clioquinol. Clioquinol-induced up-regulation of SLC30A1 (zinc exporter ZNT1) was further verified by quantitative PCR. Up-regulation of these proteins suggested that clioquinol activated metal regulatory transcription factor 1 (MTF1)-dependent transcription. We alsoexamined antioxidant 1 (ATOX1), a copper chaperone which has a redox-sensitive metal binding motif and is known to promote neuronal survival. Monitoring the redox state of ATOX1 showed clioquinol-induced thiol oxidization, possibly resulting in the inactivation of ATOX1. Collectively, dyshomeostasis of copper and zinc may be involved in the neurotoxicity of clioquinol.

Clioquinol: To harm or heal.

Clioquinol, one of the first mass-produced drugs, was considered safe and efficacious for many years. It was used as an antifungal and an antiprotozoal drug until it was linked to an outbreak of subacute myelo-optic neuropathy (SMON), a debilitating disease almost exclusively confined to Japan. Today, new information regarding clioquinol targets and its mechanism of action, as well as genetic variation (SNPs) in efflux transporters in the Japanese population, provide a unique interpretation of the existing phenomena. Further understanding of clioquinol's role in the inhibition of cAMP efflux and promoting apoptosis might offer promise for the treatment of cancer and/or neurodegenerative diseases. Here, we highlight recent developments in the field and discuss possible connections, hypotheses and perspectives in clioquinol-related research.

Clioquinol increases the expression of interleukin-8 by down-regulating GATA-2 and GATA-3

Clioquinol was used in the mid-1900s as an amebicide to treat indigestion and diarrhea. However, it was withdrawn from the market in Japan because it was linked to subacute myelo-optic neuropathy (SMON). The pathogenesis of SMON has not yet been elucidated in detail. As reported previously, we performed a global analysis on human neuroblastoma cells using DNA chips. The global analysis and quantitative PCR demonstrated that the mRNA level of interleukin-8 (IL-8) was significantly increased when SH-SY5Y neuroblastoma cells were treated with clioquinol. An enzyme-linked immunosorbent assay also demonstrated that clioquinol induced the secretion of IL-8 into culture media. Promoter analyses on SH-SY5Y cells revealed that a region responsive to clioquinol exists between –152 and –144 of the human IL-8 gene, which contains a consensus GATA-binding site sequence. The introduction of mutations at this site or the activator protein (AP)-1 site sequence at –126/–120 significantly reduced clioquinol-induced transcriptional activation. Among the GATA transcription factors expressed in SH-SY5Y cells, GATA-2 and GATA-3 protein levels were significantly decreased by the addition of clioquinol. Electrophoresis mobility shift assays using a probe corresponding to –159/–113 of the human IL-8 gene revealed two major shifted bands, one of which was increased and the other was decreased by clioquinol. The introduction of mutations showed that the former corresponded to binding to the AP-1 site, and the latter to binding to the GATA site. Supershift analyses revealed that the binding of c-Jun and c-Fos was increased, whereas that of GATA-3 was decreased by clioquinol. Genome editing against GATA-2 or GATA-3, not GATA-4 significantly enhanced clioquinol-induced IL-8 mRNA expression. On the other hand, the stable expression of GATA-2 or GATA-3 attenuated clioquinol-induced IL-8 mRNA expression and IL-8 secretion. These results suggest that the clioquinol-induced suppression of GATA-2 and GATA-3 expression mediates the up-regulation of IL-8.

P.5.f.001 - Time course of the depressive mental states in Japanese patients with subacute myelo-optic neuropathy (SMON)

P.5.f.001 - Time course of the depressive mental states in Japanese patients with subacute myelo-optic neuropathy (SMON)

The solution structure of the copper clioquinol complex

Clioquinol (5-chloro-7-iodo-8-hydroxyquinoline) recently has shown promising results in the treatment of Alzheimer's disease and in cancer therapy, both of which also are thought to be due to clioquinol's ability as a lipophilic copper chelator. Previously, clioquinol was used as an anti-fungal and anti-protozoal drug that was responsible for an epidemic of subacute myelo-optic neuropathy (SMON) in Japan during the 1960s, probably a myeloneuropathy arising from a clioquinol-induced copper deficiency. Previous X-ray absorption spectroscopy of solutions of copper chelates of clioquinol suggested unusual coordination chemistry. Here we use a combination of electron paramagnetic, UV–visible and X-ray absorption spectroscopies to provide clarification of the chelation chemistry between clioquinol and copper. We find that the solution structures for the copper complexes formed with stoichiometric and excess clioquinol are conventional 8-hydroxyquinolate chelates. Thus, the promise of clioquinol in new treatments for Alzheimer's disease and in cancer therapy is not likely to be due to any novel chelation chemistry, but rather due to other factors including the high lipophilicity of the free ligand and chelate complexes.

Clioquinol Increases the Expression of VGF, a Neuropeptide Precursor, Through Induction of c-Fos Expression

Clioquinol was used extensively in the mid-1900s as an amebicide to treat indigestion and diarrhea. It was eventually withdrawn from the market because it was linked to subacute myelo-optic neuropathy (SMON) in Japan. However, the pathogenesis of SMON has not yet been elucidated in detail. As reported previously, we performed a global analysis on human neuroblastoma cells using DNA chips. The global analysis and quantitative PCR demonstrated that the mRNA level of VGF (nonacronymic), the precursor of neuropeptides involved in pain reactions, was significantly increased when SH-SY5Y and IMR-32 neuroblastoma cells were treated with clioquinol. Promoter analyses in SH-SY5Y cells revealed that a region responsive to clioquinol exists between −1381 and −1349 of the human VGF gene, which contains an activator protein (AP)-1 site–like sequence. The introduction of mutations at this site significantly reduced clioquinol-induced transcriptional activation. Clioquinol induced the expression of the AP-1 family transcription factors, c-Jun and c-Fos. Electrophoresis mobility shift assays demonstrated that c-Jun and c-Fos could bind to the AP-1 site at −1374/−1368 in SH-SY5Y cells treated with clioquinol. RNA interference against c-Fos significantly suppressed clioquinol-induced VGF mRNA expression. These results suggest that the clioquinol-induced expression of c-Fos mediates the induction of VGF expression.

スモン患者の咳嗽力に関する検討

外来通院中のスモン患者7 名（男性2 名，女性5 名，平均年齢81.6±7.2 歳）を対象に咳嗽力の評価として，peak cough flow（以下PCF）を測定し，年齢，性別をマッチした対照群と比較した．歩行機能，Barthel Index，握力，発声持続時間も併せて測定し，PCFとの関連をスピアマンの順位相関係数およびピアソンの相関係数を用いて検討した．スモン患者群のPCFの平均値は218.6±66.2 L/min（110～300），対照群は267.1±76.3 L/min（170～360）であり，患者群で低い傾向を認めた．PCF低値の症例は，スモン患者7 名中5 名（71 ％）であった．110 L/minの症例は陳旧性肺結核の既往例であった．最長発声持続時間とPCFには強い相関を認めた．【結論】スモン患者の咳嗽力はやや低い傾向を認め，定期的な呼吸機能，咳嗽力の評価，および呼吸器合併症のリスクの軽減のための呼吸リハビリテーションの必要性が示唆された．

Clioquinol induces DNA double-strand breaks, activation of ATM, and subsequent activation of p53 signaling

Clioquinol, a Cu2+/Zn2+/Fe2+ chelator/ionophor, was used extensively in the mid 1900s as an amebicide for treating indigestion and diarrhea. It was eventually withdrawn from the market because of a link to subacute myelo-optic neuropathy (SMON) in Japan. The pathogenesis of SMON, however, is not fully understood. To clarify the molecular mechanisms of clioquinol-induced neurotoxicity, a global analysis using DNA chips was carried out on human neuroblastoma cells. The global analysis and quantitative PCR demonstrated that mRNA levels of p21Cip1, an inhibitor of cyclins D and E, and of GADD45α, a growth arrest and DNA damage-inducible protein, were significantly increased by clioquinol treatment in SH-SY5Y and IMR-32 neuroblastoma cells. Activation of p53 by clioquinol was suggested, since clioquinol induced phosphorylation of p53 at Ser15 to enhance its stabilization. The phosphorylation of p53 was inhibited by KU-55933, an inhibitor of ataxia-telangiectasia mutated kinase (ATM), but not by NU7026, an inhibitor of DNA-dependent protein kinase (DNA-PK). Clioquinol in fact induced phosphorylation of ATM and histone H2AX, a marker of DNA double-strand breaks (DSBs). These results suggest that clioquinol-induced neurotoxicity is mediated by DSBs and subsequent activation of ATM/p53 signaling.

Mesoporous Silica Nanoparticle‐based H2O2 Responsive Controlled‐Release System Used for Alzheimer's Disease Treatment

Metal ions play important roles in amyloid aggregation and neurotoxicity. Metal-ion chelation therapy has been used in clinical trials for Alzheimer's disease (AD) treatment. However, clinical trial studies have shown that long-term use of metal chelator can cause adverse side effect, subacute myelo-optic neuropathy. Nanoparticle engineering processes have become promising approaches for efficiently drugs delivery. A series of modified mesoporous silica nanoparticles (MSNs) using redox, pH, competitive binding, light, and enzyme as actuators have been demonstrated. Recently, significant advances in sensing oxidative stress have been made by taking advantage of specific chemistry between cellular oxidants such as H(2) O(2) . Here we report a biocompatible delivery platform by using H(2) O(2) responsive controlled-release system to realize target delivery of AD therapeutic metal chelator. The advantage of this novel strategy is that metal chelator can only be released by the increased levels of H(2) O(2) , thus, it would not interfere with the healthy metal homeostasis and can overcome strong side effect of metal chelator after long-term use. By taking advantage of the good biocompatibility, cellular uptake properties, and efficient intracellular release of metal chelators, the delivery system is promising for future in vivo controlled-release biomedical applications.

Clioquinol: review of its mechanisms of action and clinical uses in neurodegenerative disorders.

Clioquinol was produced as a topical antiseptic and marketed as an oral intestinal amebicide in 1934, being used to treat a wide range of intestinal diseases. In the early 1970s, it was withdrawn from the market as an oral agent because of its association with subacute myelo-optic neuropathy (SMON), a syndrome that involves sensory and motor disturbances in the lower limbs and visual changes. The first methods for determining plasma and tissue clioquinol (5-chloro-7-iodo-8-quinolinol) levels were set up in the 1970s and involved HPLC separation with UV detection, these were followed by a more sensitive GC method with electron capture detection and a gaschromatographic-massspectrometric (GC-MS) method. Finally, an HPLC method using electrochemical detection has proved to be as highly sensitive and specific as the GC-MS. In rats, mice, rabbits, and hamsters, clioquinol is rapidily absorbed and undergoes first-pass metabolization to glucuronate and sulfate conjugates; the concentrations of the metabolites are higher than those of free clioquinol. Bioavailabilty versus intraperitoneal dosing is about 12%. Dogs and monkeys form fewer conjugates. In man, single-dose concentrations are dose related, and the drug's half-life is 11-14 h. There is no accumulation, and the drug is much less metabolized to conjugates. Clioquinol acts as a zinc and copper chelator. Metal chelation is a potential therapeutic strategy for Alzheimer's disease (AD) because zinc and copper are involved in the deposition and stabilization of amyloid plaques, and chelating agents can dissolve amyloid deposits in vitro and in vivo. In general, the ability of clioquinol to chelate and redistribute metals plays an important role in diseases characterised by Zn, Cu, Fe dyshomeostasis, such as AD and Parkinson's disease, as it reduces oxidation and the amyloid burden. Zinc chelators may also act as anticancer agents. Animal toxicity studies have revealed species-specific differences in neurotoxic responses that are related to the serum levels of clioquinol and metabolites. This is also true in humans, who form fewer conjugates. The results of studies of Alzheimer patients are conflicting and need further confirmation. The potential therapeutic role of the two main effects of MPACs (the regulation of the distribution of metals and antioxidants) has not yet been fully explored.

Clioquinol Arrests Cell Cycle at G1 Phase and Triggers Intrinsic Apoptosis In Myeloma and Leukemia Cells by Inhibiting Histone Deacetylases

AbstractAbstract 1836Clioquinol (5-chloro-7-iodo-8-hydroxyquinoline, CQ) is an old and effective antifungal and amoebicidal drug but is restricted or discontinued in some countries because of its suspect causality in inducing subacute myelo-optic neuropathy, however it has been recently revitalized as an anti-cancer drug candidate at both in vitro and in vivo models. Our previous study suggested that CQ induced cell death and displayed anti-leukemia and anti-myeloma activity (Mao × et al, Leukemia, 2009), but its mechanisms are not well known. In this study, we demonstrated that clioquinol-induced cell death is via intrinsic rather than extrinsic apoptotic pathway, clioquinol-induced apoptosis depends on the activation of caspase-9 and -3. Because zinc is essential for the enzymatic activity of histone deacetylases (HDAC) which is currently emerging as a novel target for apoptotis and cancer treatment, and clioquinol is a strong chelator of zinc ion, we questioned whether clioquinol could interfere with HDAC activity by binding to zinc. Thus, we first examined the effects of clioquinol on the most often used hallmarks for HDAC inhibitions, including cyclin D, p21(CIP1), and p27(KIP1) (Nature Reviews Cancer, 2006). DNA microarray analysis indicated that clioquinol and its analogs significantly up-regulated the transcriptional level of p21 > 2–10 folds within 24 hr. The increased expression of p21(CIP1) protein was further confirmed by western blotting assay in various cell lines and primary patient samples. Clioquinol induced p21(CIP1) expression at concentrations as low as 5 μM witin 24 hr. At the same concentration, tumor suppressor and cell cycle regulator p27 (KIP1) was also increased. In addition, clioquinol also down-regulated expression of D-cyclins, including cyclin D2 and D3 in tested cell lines at a concentration consistent with that induced cell apoptosis. All these changes by clioquinol resulted in cell cycle arrest at G0/G1 phase in both leukemia and myeloma cell lines. Because these genes (cyclin D, p21 and p27) are most associated with histone acetylases, we next checked whether clioquinol is effective in inhibiting HDAC activity. Both leukemia and myeloma cell lines and primary patient samples were applied for the analysis of acetylation status of histone 3 (Ac-H3). Using trichostatin A (TSA) as a positive control, we found that clioquinol accumulated Ac-H3 in all tested cell lines and primary patient samples in a concentration- and time-dependent manner, which strongly suggested that clioquinol interfere with HDAC activity. Subsequently, we analyzed the interaction of clioquinol and HDAC. Just like TSA, clioquinol was docked into the active pocket of HDAC, where clioquinol competitively binds to zinc at the active center, which was confirmed by zinc addition. Zinc addition partially abolished the effects of clioquinol on HDAC activity. Thus, our study indicated that clioquinol-induced cell death in both leukemia and myeloma was via an apoptotic pathway by interfering with HDAC activity. Disclosures:No relevant conflicts of interest to declare.

大腿骨頸部骨折に関連する神経症状の検討―29年間のSMON検診における縦断的研究―

Hip fracture in elderly people is a major risk factor in the deterioration of activities of daily living (ADL). The aim of this study was to investigate the incidence of hip fractures and the neurological symptoms contributing to hip fracture in patients with subacute myelo-optic-neuropathy (SMON), a drug-induced neurological disease manifesting various symptoms. We investigated the incidence of hip fracture in 3,269 SMON patients with 24,187 medical check-ups from 1979 through 2007 by the SMON Research Committee in Japan. Neurological symptoms were evaluated in 80 patients who had undergone clinical examinations within 2 years before the fracture (hip-fracture group: age at examination = 75.7 ± 8.8 years (mean ± SD)), and the control group (160 SMON patients without a history of hip fracture; 76.5 ± 10.4) were matched for age, gender, and duration of illness. Incidence of hip fracture in SMON as well as severity of visual acuity, motor and sensory symptoms, and ADL were investigated. A total 230 hip fractures occurred in 208 patients (6.4%) with a men-to-women ratio of 21 : 187. In comparison with the Japanese general population, SMON patients showed a statistically high incidence of hip fracture in the 50s and 60s age groups in women (p < 0.002 in both), and in those under 40 (p < 0.02) and in their 50s (p < 0.002) in men. In those with neurological symptoms related to gait, the percentage of subjects who could walk with crutches was significantly higher in the hip-fracture group (43.8%) than in the control group (28.1%) (p < 0.05). Analysis of the vibratory sensation revealed that the hip-fracture group showed a significantly higher percentage of severe impairment (51.9%) than the control group (32.0%) (p < 0.025). There were no significant differences in variance between the two groups in other clinical symptoms or ADL. Impairment of vibration sense, a deep sensation, is more likely to be associated with falling and hip fracture than visual acuity or other neurological symptoms in SMON patients. Those persons with vibration sense disturbance, such as elderly or patients with neurological diseases, should be particularly cautious of falling.

Copper deficiency myeloneuropathy

Clioquinol, a dihalogenated derivative of 8-hydroxyquinoline, was initially developed in 1934 as a topical and intestinal antiseptic. The drug was widely used as an antiparasitic and as an over-the-counter remedy for traveler’s diarrhea. High consumption in Japan from 1950 to 1970 was associated with an epidemic of a subacute myelo-optic neuropathy (SMON). There were claims of over 10,000 cases of lower limb spasticity and sensory dysfunction with variable degrees of visual dysfunction; many were permanently disabled.1,2 Originally held to represent a viral infection, analysis of lingual green-black deposits (“green hairy tongue”) in severely affected persons disclosed high levels of an iron chelate of clioquinol. Since the drug was thought to be virtually unabsorbed from the gastrointestinal tract, safe to administer even to persons with severe lower gastrointestinal disease, and serious side effects were not reported in its initial 35 years of use, the reports of its causative role in the Japanese SMON epidemic were initially challenged. The drug was withdrawn from …

Metals in our minds: therapeutic implications for neurodegenerative disorders

Abnormal interactions of copper or iron in the brain with metal-binding proteins (such as amyloid-beta peptide [Abeta] 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 Abeta 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 Abeta(1-42), raised plasma concentrations of zinc, and-in a subset with moderate dementia-slowed cognitive decline over 24 weeks. Two recent experiments also showed the neuroprotective effects of iron chelation in a mouse model of Parkinson's disease. WHERE NEXT?: The experimental and transgenic-animal studies of metal-protein interactions are convincing but do not provide conclusive answers either about causality or whether this strategy will protect against neurodegeneration in human beings. The finding that clioquinol could modulate plasma concentrations of amyloid and cognition in patients with AD needs to be interpreted cautiously, but is an important first step. Clioquinol was withdrawn because of concerns of its association with subacute myelo-optic neuropathy in Japan; therefore, any additional studies with this drug will likely be small and closely monitored proof-of-concept studies. The development of optimal second-generation MPACs is a desirable goal and may permit greater insights into the significance of metal-protein interactions across several neurodegenerative disorders.