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. 2015 Dec;30(14):1901-1911.
doi: 10.1002/mds.26453. Epub 2015 Nov 17.

α7 nicotinic receptor agonists reduce levodopa-induced dyskinesias with severe nigrostriatal damage

Danhui Zhang #  1 , Matthew McGregor #  1 , Tanuja Bordia  1 , Xiomara A Perez  1 , J Michael McIntosh  2 , Michael W Decker  3 , Maryka Quik  1
Affiliations

α7 nicotinic receptor agonists reduce levodopa-induced dyskinesias with severe nigrostriatal damage

Danhui Zhang et al. Mov Disord. 2015 Dec.

Abstract

Background: ABT-126 is a novel, safe, and well-tolerated α7 nicotinic receptor agonist in a Phase 2 Alzheimer's disease study. We tested the antidyskinetic effect of ABT-126 in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated squirrel monkeys with moderate and more severe nigrostriatal damage.

Methods: Monkeys (n = 21, set 1) were lesioned with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine 1-2×. When parkinsonian, they were gavaged with levodopa (10 mg/kg)/carbidopa (2.5 mg/kg) twice daily and dyskinesias rated. They were then given nicotine in drinking water (n = 5), or treated with vehicle (n = 6) or ABT-126 (n = 10) twice daily orally 30 min before levodopa. Set 1 was then re-lesioned 1 to 2 times for a total of 3 to 4 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine injections. The antidyskinetic effect of ABT-126, nicotine, and the β2* nicotinic receptor agonist ABT-894 was re-assessed. Another group of monkeys (n = 23, set 2) were lesioned with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine only 1× to 2×. They were treated with levodopa/carbidopa, administered the α7 agonist ABT-107 (n = 6), ABT-894 (n = 6), nicotine (n = 5), or vehicle (n = 6) and dyskinesias evaluated. All monkeys were euthanized and the dopamine transporter measured.

Results: With moderate nigrostriatal damage (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine 1×-2×), ABT-126 dose-dependently decreased dyskinesias (∼60%), with similar results seen with ABT-894 (∼60%) or nicotine (∼60%). With more severe damage (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine 3-4×), ABT-126 and nicotine reduced dyskinesias, but ABT-894 did not. The dopamine transporter was 41% and 8.9% of control, with moderate and severe nigrostriatal damage, respectively. No drug modified parkinsonism.

Conclusion: The novel α7 nicotinic receptor drug ABT-126 reduced dyskinesias in monkeys with both moderate and severe nigrostriatal damage. ABT-126 may be useful to reduce dyskinesias in both early- and later-stage Parkinson's disease.

Keywords: ABT-126; Parkinson's disease; dyskinesia; levodopa; nicotinic.

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Figures

FIG. 1
FIG. 1
Dose-dependent decline in LIDs with the α7 nAChR agonist ABT-126 in Set 1 monkeys after they were treated with MPTP only 1-2×. Treatment timeline (A). Dose dependent decline in LIDs with ABT-126 (B). Nicotine reduces LIDs (C). Discontinuation of ABT-126 led to a return of LIDs to vehicle-treated levels (D). ABT-126 had no effect on parkinsonism off and on levodopa (E). Values are the mean ± SEM of the number of monkeys. Significantly different from vehicle, *P < 0.05, **P < 0.01, ***P < 0.001 using two-way ANOVA (A-D) or paired t-test (E).
FIG. 2
FIG. 2
ABT-126 administration reduces the hourly time course of LIDs to a similar extent with 10 (A) or 15 mg/kg levodopa after either the morning or afternoon levodopa dose (B,C) in Set 1 monkeys (MPTP 1-2×). Values were averaged over 2 sessions per wk. Both ABT-126 (1 mg/kg) and nicotine treatments are significantly different from vehicle (P < 0.05) using a Friedman test. Effect of drugs on total LID scores (right), with the line depicting the mean. Significantly different from vehicle, ##P < 0.01, ###P < 0.001 using one-way ANOVA.
FIG. 3
FIG. 3
The α7 nAChR agonist ABT-126, but not the β2* nAChR agonist ABT-894, decreases LIDs in monkeys with severe (MPTP 3-4×) nigrostriatal damage. The data in the left panels is from Set 1 monkeys administered MPTP a total of 3-4× (A-D). The data in the right panels is from Set 2 monkeys given MPTP a total of 1-2× (E-H). Treatment timelines (A,E). α7 agonists and nicotine decrease LIDs in both sets of monkeys (B,D,F,H). ABT-894 reduces LIDs only in monkeys treated with MPTP 1-2× (C,G). Values are the mean ± SEM of the number of monkeys in parenthesis. Significantly different from vehicle, #P < 0.05, ##P < 0.01, ###P < 0.001 using two-way ANOVA. ***P < 0.001, main effect of drug treatment.
FIG. 4
FIG. 4
Significantly greater decline in the dopamine transporter in all striatal areas in monkeys treated with MPTP 3-4× compared to 1-2×. Autoradiograms are shown in A and the quantitative data in B. The dotted horizontal line and grey bar represent the mean ± SEM of the transporter levels in the unlesioned monkeys (n=5). Significantly different from MPTP 1-2×, #P < 0.05, ##P < 0.01, ###P < 0.001 using two-way ANOVA. ***P < 0.001, main effect of lesioning between MTP 1-2× compared to MPTP 3-4× group.
FIG. 5
FIG. 5
Significantly greater decline in α6β2* nAChRs in all striatal areas in monkeys treated with MPTP 3-4× compared to 1-2× times. Autoradiograms are shown in A and the quantitative data in B. The dotted horizontal line and grey bar represent the mean ± SEM of α6β2* nAChR levels in unlesioned monkeys (n=5). Significantly different from MPTP 1-2×, #P < 0.05 using two-way ANOVA. *P < 0.05, **P < 0.01, main effect of lesioning between MPTP 1-2× compared to MPTP 3-4× group.
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