Methylene blue and dimebon inhibit aggregation of TDP-43 in cellular models

{ "0" : "Department of Molecular Neurobiology, Tokyo Institute of Psychiatry, Tokyo Metropolitan Organization for Medical Reearch, 2-1-8 Kamikitazawa, Setagaya-ku, Tokyo 156-8585, Japan" , "1" : "Department of Psychogeriatrics, Tokyo Institute of Psychiatry, Tokyo Metropolitan Organization for Medical Research, 2-1-8 Kamikitazawa, Setagaya-ku, Tokyo 156-8585, Japan" , "2" : "School of Biosciences, Cardiff University, Cardiff CF10 3US, UK" , "3" : "Institute of Physiologically Active Compounds, RAS, Chernogolovka 142432, Russian Federation" , "4" : "MRC Laboratory of Molecular Biology, Hills Road, Cambridge CB2 0QH, UK" , "6" : "Tau" , "7" : "Alpha-synuclein" , "8" : "Inhibitor" , "9" : "Alzheimer" , "10" : "ALS" , "11" : "FTLD"}
FEBS Letters (Impact Factor: 3.34). 07/2009; 583(14):2419-2424. DOI: 10.1016/j.febslet.2009.06.042

ABSTRACT Amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with ubiquitinated inclusions (FTLD-U) are major neurodegenerative diseases with TDP-43 pathology. Here we investigated the effects of methylene blue (MB) and dimebon, two compounds that have been reported to be beneficial in phase II clinical trials of Alzheimer’s disease (AD), on the formation of TDP-43 aggregates in SH-SY5Y cells. Following treatment with 0.05 μM MB or 5 μM dimebon, the number of TDP-43 aggregates was reduced by 50% and 45%, respectively. The combined use of MB and dimebon resulted in a 80% reduction in the number. These findings were confirmed by immunoblot analysis. The results indicate that MB and dimebon may be useful for the treatment of ALS, FTLD-U and other TDP-43 proteinopathies.

Download full-text


Available from: Sergey Bachurin, Jul 28, 2015
  • Source
    • "Despite these failings, Dimebon has continued to be tested experimentally, with several lines of recent evidence suggesting the drug indeed possesses neuroprotective activity, though the means by which protection is elicited remains obscure. Data have suggested several potential mechanisms, in particular focusing on modest changes in receptor kinetics [3] [4] [5] [6], mitochondrial activity [7] [8] [9], and an impediment in the accumulation of pathologically modified proteins [10] [11] [12] [13] [14] [15] [16] [17] [18] [19]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Dimebon has been tested as a potential modifier of Alzheimer's disease (AD), resulting in mixed clinical trial outcomes. Originally utilized as an antihistamine, Dimebon was later found to ameliorate AD symptoms in initial human trials. Although subsequent trials have reportedly failed to replicate these finding, there is a growing body of evidence that Dimebon might be neuroprotective in certain models of neurodegeneration. The precise mechanism by which Dimebon is thought to act in AD is unclear, though changes in receptor activity, mitochondria function, and autophagy activity have been proposed. It is thus necessary to test Dimebon in transgenic animal model systems to determine if and how the drug affects development and manifestation of pathology, and which pathogenic processes are altered. In the present study we treated mice harboring five familial mutations associated with hereditary AD (5xFAD line) with a chronic regime of Dimebon. The compound was not found to improve the general health or motor behavior of these mice, nor prevent accumulation of Aβ peptides in the brain. Modest changes in response to an anxiogenic task were, however, detected, suggesting Dimebon might improve behavioral abnormalities and cognition in disease in a mechanism independent of protecting against amyloidosis.
    Journal of Alzheimer's disease: JAD 05/2013; 36(3). DOI:10.3233/JAD-130071 · 4.15 Impact Factor
  • Source
    • "We have previously demonstrated that Dimebon is capable of limiting the accumulation of some aggregate prone proteins associated with neurodegeneration [10] [14]. In the tau P301S mouse model, the loss of ventral horn neurons is associated with aberrant intraneuronal accumulation of filamentous, hyperphosphorylated tau [19]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Dimebon belongs to a fast-growing group of "old" drugs that were suggested to be effective for therapy of pathological conditions different from their original targets. Following initial reports of successful Phase II clinical trials for mild-to-moderate Alzheimer's and Huntington's diseases, effects of dimebon on various neurodegenerative conditions were investigated both in follow-up clinical trials and in various model systems. Although results of Phase III clinical trials carried out so far were disappointing, there is growing body of evidence that this drug can affect neuronal physiology in a way that would be beneficial at particular stages of development of certain types of neurodegeneration. To reveal what molecular and cellular pathological processes might be affected by dimebon, we tested the ability of this drug to ameliorate pathology in model systems recapitulating particular pathogenic mechanisms involved in the development and progression of neurodegenerative diseases. Here we assessed the ability of dimebon to modify several prominent features of tauopathies using transgenic tauP301S mice as a model. Chronic treatment with dimebon was found to partially protect against the progressive decline in motor function and accumulation of tau-positive dystrophic neurons characteristic of tauP301S mice. Similar results were obtained with two further γ-carbolines structurally similar to dimebon. Our data suggest that dimebon and dimebon-like compounds might be considered as drugs possessing disease-modifying activity for diseases with prominent tau pathology.
    Journal of Alzheimer's disease: JAD 10/2012; 33(4). DOI:10.3233/JAD-2012-121732 · 4.15 Impact Factor
  • Source
    • "Consequently, the possibility that MB may have protective effects in ALS of other etiologies than mutant SOD1 could not be excluded. For instance, MB was able to clear aggregates of TDP-43 in a cellular model of ALS (Yamashita et al., 2009). In contrast, we report that MB had no effect on disease symptoms or on formation of cytoplasmic TDP-43 inclusions in transgenic mice expressing TDP-43 G348C . "
    [Show abstract] [Hide abstract]
    ABSTRACT: Approximately 20% cases of familial amyotrophic lateral sclerosis (ALS) are caused by mutations in the gene encoding Cu/Zn superoxide dismutase (SOD1). Recent studies have shown that methylene blue (MB) was efficient in conferring protection in several neurological disorders. MB was found to improve mitochondrial function, to reduce reactive oxygen species, to clear aggregates of toxic proteins, and to act as a nitric oxide synthase inhibitor. These pleiotropic effects of relevance to ALS pathogenesis led us to test MB in two models of ALS, SOD1(G93A) mice and TDP-43(G348C) transgenic mice. Intraperitoneal administration of MB at two different doses was initiated at the beginning of disease onset, at 90 days of age in SOD1(G93A) and at 6 months of age in TDP-43(G348C) mice. Despite its established neuroprotective properties, MB failed to confer protection in both mouse models of ALS. The lifespan of SOD1(G93A) mice was not affected by MB treatment. The declines in motor function, reflex score, and body weight of SOD1(G93A) mice remained unchanged. MB treatment had no effect on motor neuron loss and aggregation or misfolding of SOD1. A combination of MB with lithium also failed to provide benefits in SOD1(G93A) mice. In TDP-43(G348C) mice, MB failed to improve motor function. Cytosolic translocation of TDP-43, ubiquitination and inflammation remained also unchanged after MB treatment of TDP-43(G348C) mice.
    Neuroscience 01/2012; 209:136-43. DOI:10.1016/j.neuroscience.2011.12.047 · 3.33 Impact Factor
Show more