title: TC-8831, a nicotinic acetylcholine receptor agonist, reduces L-DOPA-induced dyskinesia in the MPTP macaque.
abstract: Long-term L-DOPA treatment for Parkinson's disease (PD) is limited by motor complications, particularly L-DOPA-induced dyskinesia (LID). A therapy with the ability to ameliorate LID without reducing anti-parkinsonian benefit would be of great value. We assessed the ability of TC-8831, an agonist at nicotinic acetylcholine receptors (nAChR) containing α6β2/α4β2 subunit combinations, to provide such benefits in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine- (MPTP) lesioned macaques with established LID. Animals were treated orally for consecutive 14-day periods with twice-daily vehicle (weeks 1-2) or TC-8831 (0.03, 0.1 or 0.3 mg/kg, weeks 3-8). L-DOPA was also administered, once-daily, (weeks 1-12, median-dose 30 mg/kg, p.o.). For the following two-weeks (weeks 9-10), TC-8831 was washed out, while once-daily L-DOPA treatment was maintained. The effects of once-daily amantadine (3 mg/kg, p.o.) were then assessed over weeks 11-12. LID, parkinsonism, duration and quality of ON-time were assessed weekly by a neurologist blinded to treatment. TC-8831 reduced the duration of 'bad' ON-time (ON-time with disabling dyskinesia) by up to 62% and decreased LID severity (median score 18 cf. 34 (vehicle), 0.1 mg/kg, 1-3 h period). TC-8831 also significantly reduced choreiform and dystonic dyskinesia (median scores 6 and 31 cf. 19 and 31 respectively (vehicle), both 0.03 mg/kg, 1-3 h). At no time did TC-8831 treatment result in a reduction in anti-parkinsonian benefit of L-DOPA. By comparison, amantadine also significantly reduced dyskinesia and decreased 'bad' ON-time (up to 61%) but at the expense of total ON-time (reduced by up to 23%). TC-8831 displayed robust anti-dyskinetic actions and improved the quality of ON-time evoked by L-DOPA without any reduction in anti-parkinsonian benefit.
authors.affiliation: Toronto Western Research Institute, Toronto Western Hospital, University Health Network, Toronto, ON, Canada.
authors.forename: Tom H
authors.initials: TH
authors.lastname: Johnston
authors.forename: Philippe
authors.initials: P
authors.lastname: Huot
authors.forename: Susan H
authors.initials: SH
authors.lastname: Fox
authors.forename: James B
authors.initials: JB
authors.lastname: Koprich
authors.forename: Kendall T
authors.initials: KT
authors.lastname: Szeliga
authors.forename: John W
authors.initials: JW
authors.lastname: James
authors.forename: John D
authors.initials: JD
authors.lastname: Graef
authors.forename: Sharon R
authors.initials: SR
authors.lastname: Letchworth
authors.forename: Kristen G
authors.initials: KG
authors.lastname: Jordan
authors.forename: Michael P
authors.initials: MP
authors.lastname: Hill
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Brotchie
mesh_terms: D000547:Amantadine / Q000627:therapeutic use; D000818:Animals; D053961:Azabicyclo Compounds / Q000627:therapeutic use*; D003521:Cyclopropanes / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D004409:Dyskinesia, Drug-Induced / Q000150:complications / Q000188:drug therapy*; D005260:Female; D007980:Levodopa; D020267:MPTP Poisoning / Q000150:complications / Q000188:drug therapy*; D008252:Macaca fascicularis; D018722:Nicotinic Agonists / Q000627:therapeutic use*
chemical_list: D053961:Azabicyclo Compounds; D003521:Cyclopropanes; D018722:Nicotinic Agonists; C588225:TC-8831; D007980:Levodopa; D000547:Amantadine
keywords: Dyskinesia; MPTP; Primate; nAchR