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

E Hockly; J Tse; A L Barker; D L Moolman; J L Beunard; A P Revington; K Holt; S Sunshine; H Moffitt; K Sathasivum; B Woodman; E E Wanker; P A Lowden; G P Bates

doi:10.1016/j.nbd.2005.07.007

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

E Hockly, J Tse, A L Barker, D L Moolman, J L Beunard, A P Revington, K Holt, S Sunshine, H Moffitt, K Sathasivum, B Woodman, E E Wanker, P A Lowden, G P Bates

Medical & Molecular Genetics

Research output: Contribution to journal › Article › peer-review

78 Citations (Scopus)

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 mu M 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 mu M in brain. However, this was insufficient to inhibit aggregation in vivo and we found no improvement in the disease phenotype. (c) 2005 Elsevier Inc. All rights reserved

Original language	English
Pages (from-to)	228 - 236
Number of pages	9
Journal	Neurobiology of Disease
Volume	21
Issue number	1
DOIs	https://doi.org/10.1016/j.nbd.2005.07.007
Publication status	Published - Jan 2006

Access to Document

10.1016/j.nbd.2005.07.007

Cite this

Hockly, E., Tse, J., Barker, A. L., Moolman, D. L., Beunard, J. L., Revington, A. P., Holt, K., Sunshine, S., Moffitt, H., Sathasivum, K., Woodman, B., Wanker, E. E., Lowden, P. A., & 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), 228 - 236. https://doi.org/10.1016/j.nbd.2005.07.007

@article{6309a54a10424ad2af53600c93aff3f4,

title = "Evaluation of the benzothiazole aggregation inhibitors riluzole and PGL-135 as therapeutics for Huntington's disease.",

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 mu M 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 mu M in brain. However, this was insufficient to inhibit aggregation in vivo and we found no improvement in the disease phenotype. (c) 2005 Elsevier Inc. All rights reserved",

author = "E Hockly and J Tse and Barker, {A L} and Moolman, {D L} and Beunard, {J L} and Revington, {A P} and K Holt and S Sunshine and H Moffitt and K Sathasivum and B Woodman and Wanker, {E E} and Lowden, {P A} and Bates, {G P}",

year = "2006",

month = jan,

doi = "10.1016/j.nbd.2005.07.007",

language = "English",

volume = "21",

pages = "228 -- 236",

journal = "Neurobiology of Disease",

publisher = "Elsevier",

number = "1",

}

Hockly, E , Tse, J , Barker, AL, Moolman, DL, Beunard, JL, Revington, AP, Holt, K, Sunshine, S, Moffitt, H , Sathasivum, K , Woodman, B, Wanker, EE, Lowden, PA & Bates, GP 2006, 'Evaluation of the benzothiazole aggregation inhibitors riluzole and PGL-135 as therapeutics for Huntington's disease.', Neurobiology of Disease, vol. 21, no. 1, pp. 228 - 236. https://doi.org/10.1016/j.nbd.2005.07.007

TY - JOUR

T1 - Evaluation of the benzothiazole aggregation inhibitors riluzole and PGL-135 as therapeutics for Huntington's disease.

AU - Hockly, E

AU - Tse, J

AU - Barker, A L

AU - Moolman, D L

AU - Beunard, J L

AU - Revington, A P

AU - Holt, K

AU - Sunshine, S

AU - Moffitt, H

AU - Sathasivum, K

AU - Woodman, B

AU - Wanker, E E

AU - Lowden, P A

AU - Bates, G P

PY - 2006/1

Y1 - 2006/1

N2 - 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 mu M 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 mu M in brain. However, this was insufficient to inhibit aggregation in vivo and we found no improvement in the disease phenotype. (c) 2005 Elsevier Inc. All rights reserved

AB - 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 mu M 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 mu M in brain. However, this was insufficient to inhibit aggregation in vivo and we found no improvement in the disease phenotype. (c) 2005 Elsevier Inc. All rights reserved

U2 - 10.1016/j.nbd.2005.07.007

DO - 10.1016/j.nbd.2005.07.007

M3 - Article

VL - 21

SP - 228

EP - 236

JO - Neurobiology of Disease

JF - Neurobiology of Disease

IS - 1

ER -

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

Abstract

Access to Document

Fingerprint

Cite this