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. 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. © 2015 International Parkinson and Movement Disorder Society