title: α7 nicotinic receptor agonists reduce levodopa-induced dyskinesias with severe nigrostriatal damage.
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.
  
  
  CONCLUSIONS
  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.affiliation: Center for Health Sciences, SRI International, 333 Ravenswood Ave, Menlo Park, CA, 94025.
authors.forename: Danhui
authors.initials: D
authors.lastname: Zhang
authors.affiliation: Center for Health Sciences, SRI International, 333 Ravenswood Ave, Menlo Park, CA, 94025.
authors.forename: Matthew
authors.initials: M
authors.lastname: McGregor
authors.affiliation: Center for Health Sciences, SRI International, 333 Ravenswood Ave, Menlo Park, CA, 94025.
authors.forename: Tanuja
authors.initials: T
authors.lastname: Bordia
authors.affiliation: Center for Health Sciences, SRI International, 333 Ravenswood Ave, Menlo Park, CA, 94025.
authors.forename: Xiomara A
authors.initials: XA
authors.lastname: Perez
authors.affiliation: George E. Wahlen Veterans Affairs Medical Center and Departments of Psychiatry and Biology, University of Utah, Salt Lake City, UT 84148.
authors.forename: J Michael
authors.initials: JM
authors.lastname: McIntosh
authors.affiliation: AbbVie, Inc, 1 North Waukegan Road, North Chicago, IL 60064-6125.
authors.forename: Michael W
authors.initials: MW
authors.lastname: Decker
authors.affiliation: Center for Health Sciences, SRI International, 333 Ravenswood Ave, Menlo Park, CA, 94025.
authors.forename: Maryka
authors.initials: M
authors.lastname: Quik
mesh_terms: D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D000818:Animals; D000978:Antiparkinson Agents / Q000009:adverse effects* / Q000627:therapeutic use; D004409:Dyskinesia, Drug-Induced / Q000188:drug therapy* / Q000473:pathology; D005260:Female; D007980:Levodopa / Q000009:adverse effects* / Q000627:therapeutic use; D008297:Male; D018722:Nicotinic Agonists / Q000494:pharmacology / Q000627:therapeutic use*; D020734:Parkinsonian Disorders / Q000188:drug therapy* / Q000473:pathology; D012453:Saimiri; D013378:Substantia Nigra / Q000473:pathology*; D064569:alpha7 Nicotinic Acetylcholine Receptor / Q000819:agonists*
chemical_list: D000978:Antiparkinson Agents; D018722:Nicotinic Agonists; D064569:alpha7 Nicotinic Acetylcholine Receptor; D007980:Levodopa; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine
keywords: ABT-126; Parkinson's disease; dyskinesia; levodopa; nicotinic