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. 2014 Apr;29(4):508-17.
doi: 10.1002/mds.25817. Epub 2014 Feb 11.

ABT-089 and ABT-894 reduce levodopa-induced dyskinesias in a monkey model of Parkinson's disease

Danhui Zhang  1 , Tanuja Bordia, Matthew McGregor, J Michael McIntosh, Michael W Decker, Maryka Quik
Affiliations

ABT-089 and ABT-894 reduce levodopa-induced dyskinesias in a monkey model of Parkinson's disease

Danhui Zhang et al. Mov Disord. 2014 Apr.

Abstract

Levodopa-induced dyskinesias (LIDs) are a serious complication of levodopa therapy for Parkinson's disease for which there is little treatment. Accumulating evidence shows that nicotinic acetylcholine receptor (nAChR) drugs decrease LIDs in parkinsonian animals. Here, we examined the effect of two β2 nAChR agonists, ABT-089 and ABT-894, that previously were approved for phase 2 clinical trials for other indications. Two sets of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned monkeys were administered levodopa/carbidopa (10 mg/kg and 2.5 mg/kg, respectively) twice daily 5 days a week until they were stably dyskinetic. Each set had a vehicle-treated group, an nAChR agonist-treated group, and a nicotine-treated group as a positive control. Set A monkeys had previously received other nAChR drugs (nAChR drug-primed), whereas Set B monkeys were initially nAChR drug-naive. Both sets were administered the partial agonist ABT-089 (range, 0.01-1.0 mg/kg) orally 5 days a week twice daily 30 minutes before levodopa with each dose given for 1 to 5 weeks. ABT-089 decreased LIDs by 30% to 50% compared with vehicle-treated monkeys. Nicotine reduced LIDs by 70% in a parallel group. After 4 weeks of washout, the effect of the full agonist ABT-894 (range, 0.0001-0.10 mg/kg) was assessed on LIDs in Set A and Set B. ABT-894 reduced LIDs by 70%, similar to nicotine. Both drugs acted equally well at α4β2* and α6β2* nAChRs; however, ABT-089 was 30 to 60 times less potent than ABT-894. Tolerance did not develop for the time periods tested (range, 3-4 months). The nAChR drugs did not worsen parkinsonism or cognitive ability. Emesis, a common problem with nAChR drugs, was not observed. ABT-894 and ABT-089 appear to be good candidate nAChR drugs for the management of LIDs in Parkinson's disease.

Keywords: ABT-089; ABT-894; Parkinson's disease; dyskinesia; levodopa; nicotinic.

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Figures

FIG. 1
FIG. 1
The partial β2* nAChR agonist ABT-089 similarly decreases LIDs in monkeys previously treated with nAChR drugs (Set A) and in nAChR drug-naïve monkeys (Set B). Drug washout led to a return of LIDs to vehicle-treated values. Values are the mean ± SEM of 5-6 monkeys. Significantly different from vehicle by ANOVA, *P < 0.05, **P < 0.01, ***P < 0.001.
FIG. 2
FIG. 2
The partial β2* nAChR agonist ABT-089 and the full β2* nAChR agonist ABT-894 decrease the hourly time course of LIDs in monkeys previously treated with nAChR drugs (Set A) and drug-naïve monkeys (Set B). The symbols depict the median of 5-6 monkeys in the line graphs. In the scatter plots, the symbols represent the total dyskinesia score of individual monkeys and the bars the mean values. Significantly different from vehicle using a Mann-Whitney test, *P < 0.05, **P < 0.01, ***P < 0.001. Significantly different from vehicle using a t-test, #P < 0.05, ##P < 0.01, ###P < 0.001.
FIG. 3
FIG. 3
The full β2* nAChR agonist ABT-894 decreases LIDs to a greater extent than ABT-089 in both Set A and Set B. Drug washout led to a return of LIDs to vehicle-treated values. Values are the mean ± SEM of 5-6 monkeys. Significantly different from vehicle, **P < 0.01, ***P < 0.001 using ANOVA.
FIG. 4
FIG. 4
The partial β2* nAChR agonist ABT-089 and the full β2* nAChR agonist ABT-894 do not affect Parkinsonism assessed before and 90 min after L-dopa administration (upper panels). The symbols represent the score of individual monkeys and the bars the median value. There were also no changes in cognitive performance (lower panels), with the bars representing the mean ± SEM of 5-6 monkeys.
FIG. 5
FIG. 5
Greater potency of ABT-894 as compared to ABT-089 in receptor competition studies. Each drug interacts with a similar potency at α4β2* and α6β2* nAChRs, as assessed from 125I-epibatidine and 125I-α-conotoxinMII inhibition studies. Values are the mean ± SEM of 4 animals.
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