Multiple CNS nicotinic receptors mediate L-dopa-induced dyskinesias: studies with parkinsonian nicotinic receptor knockout mice.
Multiple CNS nicotinic receptors mediate L-dopa-induced dyskinesias: studies with parkinsonian nicotinic receptor knockout mice.
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DOI：
10.1016/j.bcp.2013.06.027
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发表时间：
2013-10-15
影响因子：
5.8
通讯作者：
Grady, Sharon R.
中科院分区：
文献类型：
--
作者：
Quik, Maryka;Campos, Carla;Grady, Sharon R.
越来越多的证据支持这样的观点，即作用于烟碱型乙酰胆碱受体(NAChRs)的药物可能对帕金森病有益。帕金森病是一种神经退行性运动障碍，其特征是黑质纹状体多巴胺能神经元的丧失。给帕金森病动物注射尼古丁可以保护黑质纹状体免受损害。此外，尼古丁和nAChR药物还可以改善L-多巴引起的运动障碍，这是L-多巴疗法的一种衰弱副作用，目前仍是治疗帕金森氏症的黄金标准。尼古丁通过与多种nAChRs相互作用发挥抗运动障碍的作用。识别L-多巴诱导的运动障碍亚型的一种方法是通过使用nAChR亚单位缺失突变小鼠。先前对β2和α6nAChR基因敲除小鼠的研究表明，α6β2*nAChR在L多巴诱导的异常不自主运动(AIMS)的发生和维持中是必需的。目前在帕金森病α4nAChR基因敲除小鼠中的结果表明，α4β2*nAChRs也起着重要作用，因为尼古丁不能减少L多巴诱导的AIMS。对α4和α6基因敲除小鼠数据的联合分析表明，α6α4β2β3亚型可能是关键。与α4和α6基因敲除小鼠的研究相比，尼古丁治疗确实减少了L多巴在帕金森病α7nAChR基因敲除小鼠中诱导的AIMS。然而，α7nAChR亚基缺失单独增加了基线AIMS，提示α7受体对L多巴诱导的AIMS有抑制作用。综上所述，α6β2*、α4β2*和α7 nAChRs均可调节L诱导的AIMS，尽管它们的调节模式不同。因此，靶向一个或多个nAChR的药物可能是减少L-多巴诱导的帕金森病运动障碍的最佳药物。
Accumulating evidence supports the idea that drugs acting at nicotinic acetylcholine receptors (nAChRs) may be beneficial for Parkinson's disease, a neurodegenerative movement disorder characterized by a loss of nigrostriatal dopaminergic neurons. Nicotine administration to parkinsonian animals protects against nigrostriatal damage. In addition, nicotine and nAChR drugs improve L-dopa-induced dyskinesias, a debilitating side effect of L-dopa therapy which remains the gold-standard treatment for Parkinson's disease. Nicotine exerts its antidyskinetic effect by interacting with multiple nAChRs. One approach to identify the subtypes specifically involved in L-dopa-induced dyskinesias is through the use of nAChR subunit null mutant mice. Previous work with β2 and α6 nAChR knockout mice has shown that α6β2* nAChRs were necessary for the development/maintenance of L-dopa-induced abnormal involuntary movements (AIMs). The present results in parkinsonian α4 nAChR knockout mice indicate that α4β2* nAChRs also play an essential role since nicotine did not reduce L-dopa-induced AIMs in such mice. Combined analyses of the data from α4 and α6 knockout mice suggest that the α6α4β2β3 subtype may be critical. In contrast to the studies with α4 and α6 knockout mice, nicotine treatment did reduce L-dopa-induced AIMs in parkinsonian α7 nAChR knockout mice. However, α7 nAChR subunit deletion alone increased baseline AIMs, suggesting that α7 receptors exert an inhibitory influence on L-dopa-induced AIMs. In conclusion, α6β2*, α4β2* and α7 nAChRs all modulate L-dopa-induced AIMs, although their mode of regulation varies. Thus drugs targeting one or multiple nAChRs may be optimal for reducing L-dopa-induced dyskinesias in Parkinson's disease.
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影响因子：
1.6
作者：
Fowler CD;Arends MA;Kenny PJ
通讯作者：
Kenny PJ
影响因子：
3.6
作者：
Kaiser, S;Wonnacott, S
通讯作者：
Wonnacott, S
影响因子：
--
作者：
Cenci, M. Angela;Konradi, Christine
通讯作者：
Konradi, Christine
DOI：
10.1124/jpet.111.182949
发表时间：
2011-09-01
影响因子：
3.5
作者：
Huang, Luping Z.;Grady, Sharon R.;Quik, Maryka
通讯作者：
Quik, Maryka
影响因子：
4.7
作者：
Huang, Luping Z.;Campos, Carla;Ly, Jason;Carroll, F. Ivy;Quik, Maryka
通讯作者：
Quik, Maryka