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α7 nicotinic receptor agonists reduce levodopa-induced dyskinesias with severe nigrostriatal damage.
Mov Disord. 2015 Dec; 30(14):1901-1911.MD

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.

Authors+Show Affiliations

Center for Health Sciences, SRI International, 333 Ravenswood Ave, Menlo Park, CA, 94025.Center for Health Sciences, SRI International, 333 Ravenswood Ave, Menlo Park, CA, 94025.Center for Health Sciences, SRI International, 333 Ravenswood Ave, Menlo Park, CA, 94025.Center for Health Sciences, SRI International, 333 Ravenswood Ave, Menlo Park, CA, 94025.George E. Wahlen Veterans Affairs Medical Center and Departments of Psychiatry and Biology, University of Utah, Salt Lake City, UT 84148.AbbVie, Inc, 1 North Waukegan Road, North Chicago, IL 60064-6125.Center for Health Sciences, SRI International, 333 Ravenswood Ave, Menlo Park, CA, 94025.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

26573698

Citation

Zhang, Danhui, et al. "Α7 Nicotinic Receptor Agonists Reduce Levodopa-induced Dyskinesias With Severe Nigrostriatal Damage." Movement Disorders : Official Journal of the Movement Disorder Society, vol. 30, no. 14, 2015, pp. 1901-1911.
Zhang D, McGregor M, Bordia T, et al. Α7 nicotinic receptor agonists reduce levodopa-induced dyskinesias with severe nigrostriatal damage. Mov Disord. 2015;30(14):1901-1911.
Zhang, D., McGregor, M., Bordia, T., Perez, X. A., McIntosh, J. M., Decker, M. W., & Quik, M. (2015). Α7 nicotinic receptor agonists reduce levodopa-induced dyskinesias with severe nigrostriatal damage. Movement Disorders : Official Journal of the Movement Disorder Society, 30(14), 1901-1911. https://doi.org/10.1002/mds.26453
Zhang D, et al. Α7 Nicotinic Receptor Agonists Reduce Levodopa-induced Dyskinesias With Severe Nigrostriatal Damage. Mov Disord. 2015;30(14):1901-1911. PubMed PMID: 26573698.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - α7 nicotinic receptor agonists reduce levodopa-induced dyskinesias with severe nigrostriatal damage. AU - Zhang,Danhui, AU - McGregor,Matthew, AU - Bordia,Tanuja, AU - Perez,Xiomara A, AU - McIntosh,J Michael, AU - Decker,Michael W, AU - Quik,Maryka, Y1 - 2015/11/17/ PY - 2015/07/23/received PY - 2015/09/09/revised PY - 2015/09/16/accepted PY - 2015/11/18/entrez PY - 2015/11/18/pubmed PY - 2017/1/11/medline KW - ABT-126 KW - Parkinson's disease KW - dyskinesia KW - levodopa KW - nicotinic SP - 1901 EP - 1911 JF - Movement disorders : official journal of the Movement Disorder Society JO - Mov Disord VL - 30 IS - 14 N2 - 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. SN - 1531-8257 UR - https://www.unboundmedicine.com/medline/citation/26573698/α7_nicotinic_receptor_agonists_reduce_levodopa_induced_dyskinesias_with_severe_nigrostriatal_damage_ DB - PRIME DP - Unbound Medicine ER -