Article

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: 3.17). 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.

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    • "In most cases the in vitro assays showed aggregation inhibition, while the therapeutic effects of MB in cell culture and animal models of proteinopathies has proven to be more complex and sometimes contradictory. In cell culture assays, MB is able to reduce aggregation of Tau, TDP-43 and Htt [144,147,150], however, no effect on PrP scrapie formation was observed in this type of assay [151]. This compound is approved by the US Food and Drug Administration for oral and intravenous administration in different diseases. "

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    • "Sin embargo, cuando Shelkovnikova et al trataron ratones αSyn (1-120) TG, modelo que remeda etapas tempranas de la enfermefad de Parkinson, con latrepirdina incluida en el agua de la bebida, no hallaron diferencias en la actividad locomotora espontánea [41]. La latrepirdina ha presentado también efectos antiagregantes en otros modelos celulares, como los que sobreexpresan la proteína TAR de 43 kDa (TDP-43) [42], la cual actúa de unión al ADN y se relaciona con diferentes trastornos neurodegenerativos (enfermedad de Alzheimer, enfermedad de Huntington , síndrome de Perry, esclerosis lateral amiotrófica , demencia por cuerpos de Lewy, etc.) [43]. Sin embargo, Bachurin et al, utilizando como modelo de proteinopatía el ratón Thy1mγSN, el cual presenta una alta sobreexpresión de γ-sinucleína, y administrando latrepirdina (10 μg/kg) en el agua de la bebida, demostraron una mejora en la actividad motora a los tres y seis meses de tratamiento, observando una clara disminución del número de inclusiones de amiloide [44]. "
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    ABSTRACT: We conduct a systematic review of the preclinical studies published to date involving the use of latrepirdine (Dimebon ®). Latrepirdine is capable of modulating different targets, such as those related with mitochondria, acetylcholinesterase activity or intraneuronal calcium levels, perhaps thanks to its action upon the N-methyl-D-aspartate-type receptor, which belongs to the glutamate family. The findings published on the possible effect of latrepirdine in protein aggregation processes in disorders such as Alzheimer's disease and Parkinson's disease are quite controversial. Likewise, the possible neuroprotective effect of latrepirdine has been evaluated in animal models of neurodegenerative diseases, again with heterogeneous results. Consequently, it can be concluded that no preclinical scientific evidence has been found to justify carrying out clinical trials.
    Full-text · Article · Jan 2015 · Revista de neurologia
    • "In most cases the in vitro assays showed aggregation inhibition, while the therapeutic effects of MB in cell culture and animal models of proteinopathies has proven to be more complex and sometimes contradictory. In cell culture assays, MB is able to reduce aggregation of Tau, TDP-43 and Htt [144,147,150], however, no effect on PrP scrapie formation was observed in this type of assay [151]. This compound is approved by the US Food and Drug Administration for oral and intravenous administration in different diseases. "
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    ABSTRACT: Impaired proteostasis is one of the main features of all amyloid diseases, which are associated with the formation of insoluble aggregates from amyloidogenic proteins. The aggregation process can be caused by overproduction or poor clearance of these proteins. However, numerous reports suggest that amyloid oligomers are the most toxic species, rather than insoluble fibrillar material, in Alzheimer's, Parkinson's, and Prion diseases, among others. Although the exact protein that aggregates varies between amyloid disorders, they all share common structural features that can be used as therapeutic targets. In this review, we focus on therapeutic approaches against shared features of toxic oligomeric structures and future directions.
    No preview · Article · Jan 2014 · Biochemical pharmacology
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