TC-8831, a nicotinic acetylcholine receptor agonist, reduces l-DOPA-induced dyskinesia in the MPTP macaque

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• 作者：Tom H. Johnston ; Philippe Huot ; Susan H. Fox ; James B. Koprich ; Kendall T. Szeliga ; John W. James ; John D. Graef ; Sharon R. Letchworth ; Kristen G. Jordan ; Michael P. Hill ; Jonathan M. Brotchie
• 关键词：Dyskinesia ; Primate ; MPTP ; nAchR
• 刊名：Neuropharmacology
• 出版年：2013
• 出版时间：October, 2013
• 年：2013
• 卷：73
• 期：Complete
• 页码：337-347
• 全文大小：1319 K

文摘

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 ¦Á6¦Â2/¦Á4¦Â2 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.