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 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.
authors.affiliation: 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.
authors.forename: Emma
authors.initials: E
authors.lastname: Hockly
authors.forename: Jamie
authors.initials: J
authors.lastname: Tse
authors.forename: Amy L
authors.initials: AL
authors.lastname: Barker
authors.forename: Donna L
authors.initials: DL
authors.lastname: Moolman
authors.forename: Jean-Luc
authors.initials: JL
authors.lastname: Beunard
authors.forename: Adrian P
authors.initials: AP
authors.lastname: Revington
authors.forename: Kim
authors.initials: K
authors.lastname: Holt
authors.forename: Sunny
authors.initials: S
authors.lastname: Sunshine
authors.forename: Hilary
authors.initials: H
authors.lastname: Moffitt
authors.forename: Kirupa
authors.initials: K
authors.lastname: Sathasivam
authors.forename: Benjamin
authors.initials: B
authors.lastname: Woodman
authors.forename: Erich E
authors.initials: EE
authors.lastname: Wanker
authors.forename: Philip A S
authors.initials: PA
authors.lastname: Lowden
authors.forename: Gillian P
authors.initials: GP
authors.lastname: Bates
mesh_terms: 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*
chemical_list: D052160:Benzothiazoles; D018696:Neuroprotective Agents; C508410:PGL-135; D013844:Thiazoles; D019782:Riluzole; C005465:benzothiazole