Evaluation of the benzothiazole aggregation inhibitors riluzole and PGL-135 as therapeutics for Huntington's disease.
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 microM 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 microM in brain. However, this was insufficient to inhibit aggregation in vivo and we found no improvement in the disease phenotype.
Hockly
Emma
E
King's College London, Department of Medical and Molecular Genetics, GKT School of Medicine, 8th Floor Guy's Tower, Guy's Hospital, London SE1 9RT, UK.
Tse
Jamie
J
Barker
Amy L
AL
Moolman
Donna L
DL
Beunard
Jean-Luc
JL
Revington
Adrian P
AP
Holt
Kim
K
Sunshine
Sunny
S
Moffitt
Hilary
H
Sathasivam
Kirupa
K
Woodman
Benjamin
B
Wanker
Erich E
EE
Lowden
Philip A S
PA
Bates
Gillian P
GP
D000818:Animals; D052160:Benzothiazoles; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005260:Female; D005838:Genotype; D006816:Huntington Disease / Q000188:drug therapy* / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D008822:Mice, Transgenic; D018696:Neuroprotective Agents / Q000737:chemistry / Q000493:pharmacokinetics*; D009924:Organ Culture Techniques; D019782:Riluzole / Q000737:chemistry / Q000493:pharmacokinetics*; D013844:Thiazoles / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*
D052160:Benzothiazoles; D018696:Neuroprotective Agents; C508410:PGL-135; D013844:Thiazoles; D019782:Riluzole; C005465:benzothiazole