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    Evaluation of the benzothiazole aggregation inhibitors riluzole and PGL-135 as therapeutics for Huntington's disease

    Hockly, E. and Tse, J. and Barker, A.L. and Moolman, D.L. and Beunard, Jean-Luc and Revington, Adrian P. and Holt, K. and Sunshine, S. and Moffitt, H. and Sathasivam, K. and Woodman, B. and Wanker, E.E. and Lowden, Philip A.S. and Bates, G.P. (2006) Evaluation of the benzothiazole aggregation inhibitors riluzole and PGL-135 as therapeutics for Huntington's disease. Neurobiology of Disease 21 (1), pp. 228-236. ISSN 0969-9961.

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    Huntington's disease (HD) is an inherited progressive neurological disorder for which there is no effective therapy. It is caused by a CAG/polyglutamine repeat expansion that leads to abnormal protein aggregation and deposition in the brain. Several compounds have been shown to disrupt the aggregation process in vitro, including a number of benzothiazoles. To further explore the therapeutic potential of the benzothiazole aggregation inhibitors, we assessed PGL-135 and riluzole in hippocampal slice cultures derived from the R6/2 mouse, confirming their ability to inhibit aggregation with an EC50 of 40 μM in this system. Preliminary pharmacological work showed that PGL-135 was metabolically unstable, and therefore, we conducted a preclinical trial in the R6/2 mouse with riluzole. At the maximum tolerated dose, we achieved steady-state riluzole levels of 100 μM in brain. However, this was insufficient to inhibit aggregation in vivo and we found no improvement in the disease phenotype.


    Item Type: Article
    Keyword(s) / Subject(s): Huntington's disease, Polyglutamine, neurodegeneration, aggregation inhibitor, Benzothiazole, Riluzole, R6/2
    School: Birkbeck Faculties and Schools > Faculty of Science > School of Natural Sciences
    Research Centres and Institutes: Structural Molecular Biology, Institute of (ISMB)
    Depositing User: Administrator
    Date Deposited: 12 Aug 2011 08:37
    Last Modified: 02 Aug 2023 16:55


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