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.

Keywords: Dyskinesia; MPTP; Primate; nAchR.