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

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Item Type:	Article
Title:	Evaluation of the benzothiazole aggregation inhibitors riluzole and PGL-135 as therapeutics for Huntington's disease
Creators Name:	Hockly, E., Tse, J., Barker, A.L., Moolman, D.L., Beunard, J.L., Revington, A.P., Holt, K., Sunshine, S., Moffitt, H., Sathasivam, K., Woodman, B., Wanker, E.E., Lowden, P.A. and Bates, G.P.
Abstract:	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.
Keywords:	Aggregation Inhibitor, Benzothiazole, Huntingtons Disease, Neurodegeneration, Polyglutamine, R6/2, Riluzole, Animals, Mice
Source:	Neurobiology of Disease
ISSN:	0969-9961
Publisher:	Elsevier
Volume:	21
Number:	1
Page Range:	228-236
Date:	January 2006
Official Publication:	https://doi.org/10.1016/j.nbd.2005.07.007
PubMed:	View item in PubMed

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