α7烟碱受体激动剂可减轻伴有严重黑质纹状体损伤的左旋多巴诱发的异动症。
α7 nicotinic receptor agonists reduce levodopa-induced dyskinesias with severe nigrostriatal damage.
作者信息
Zhang Danhui, McGregor Matthew, Bordia Tanuja, Perez Xiomara A, McIntosh J Michael, Decker Michael W, Quik Maryka
机构信息
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.
出版信息
Mov Disord. 2015 Dec;30(14):1901-1911. doi: 10.1002/mds.26453. Epub 2015 Nov 17.
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.
背景
ABT - 126是一种新型、安全且耐受性良好的α7烟碱受体激动剂，正处于阿尔茨海默病的2期研究中。我们在经1 - 甲基 - 4 - 苯基 - 1,2,3,6 - 四氢吡啶处理、具有中度及更严重黑质纹状体损伤的松鼠猴中测试了ABT - 126的抗运动障碍作用。
方法
猴子（n = 21，第1组）用1 - 甲基 - 4 - 苯基 - 1,2,3,6 - 四氢吡啶进行1 - 2次损伤。出现帕金森症状后，它们每天两次灌胃左旋多巴（10 mg/kg）/卡比多巴（2.5 mg/kg），并对运动障碍进行评分。然后，它们在饮用水中给予尼古丁（n = 5），或用赋形剂处理（n = 6），或在左旋多巴给药前30分钟每天两次口服ABT - 126（n = 10）。然后第1组再进行1至2次损伤，总共进行3至4次1 - 甲基 - 4 - 苯基 - 1,2,3,6 - 四氢吡啶注射。重新评估ABT - 126、尼古丁和β2*烟碱受体激动剂ABT - 894的抗运动障碍作用。另一组猴子（n = 23，第2组）仅用1 - 甲基 - 4 - 苯基 - 1,2,3,6 - 四氢吡啶进行1至2次损伤。它们接受左旋多巴/卡比多巴治疗，给予α7激动剂ABT - 107（n = 6）、ABT - 894（n = 6）、尼古丁（n = 5）或赋形剂（n = 6），并评估运动障碍。所有猴子均实施安乐死并测量多巴胺转运体。
结果
在中度黑质纹状体损伤（1 - 甲基 - 4 - 苯基 - 1,2,3,6 - 四氢吡啶1至2次）时，ABT - 126剂量依赖性地减少运动障碍（约60%），ABT - 894（约60%）或尼古丁（约60%）也有类似结果。在更严重损伤（1 - 甲基 - 4 - 苯基 - 1,2,3,6 - 四氢吡啶3至4次）时，ABT - 126和尼古丁减少了运动障碍，但ABT - 894没有。中度和严重黑质纹状体损伤时，多巴胺转运体分别为对照的41%和8.9%。没有药物改善帕金森症状。
结论
新型α7烟碱受体药物ABT - 126可减少中度和严重黑质纹状体损伤猴子的运动障碍。ABT - 126可能有助于减少早期和晚期帕金森病的运动障碍。
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