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

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 -