Partial recovery of striatal nicotinic receptors in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned monkeys with chronic oral nicotine
Partial recovery of striatal nicotinic receptors in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned monkeys with chronic oral nicotine
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DOI：
10.1124/jpet.106.106997
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发表时间：
2006-10-01
影响因子：
3.5
通讯作者：
Quik, Maryka
中科院分区：
文献类型：
--
作者：
Bordia, Tanuja;Parameswaran, Neeraja;Quik, Maryka
最近对非人类灵长类动物的研究表明，长期尼古丁治疗可以防止黑质纹状体变性，部分恢复纹状体的神经化学和功能测量。目前的研究旨在确定长期尼古丁治疗是否也能防止黑质纹状体损伤后纹状体烟碱受体（nAChR）的损失。猴子在饮用水中服用尼古丁 6 个月，随后在持续服用尼古丁的同时，在几个月内用多巴胺能神经毒素 1-甲基-4-苯基-1,2,3,6-四氢吡啶 (MPTP) 造成损害。采用 I-125-Epibatidine、[I-125] 5-[I-125] iodo-3(2(S)-azetidinylmethoxy)pyridine (A85380) 和 I-125-α-芋螺毒素 MII 进行放射自显影，以评估 α 4 β 2* 和 α 3/α 6 β 2* nAChR（主要纹状体）的变化。亚型。尼古丁治疗使未病变和病变动物纹状体中的 α 4 β 2* nAChR 增加≥ 50%。与未损伤的猴纹状体相比，损伤的猴纹状体中α4β2*nAChRs的增加显着更大。长期尼古丁治疗导致 α 3/α 6 beta 2* nAChR 亚型小幅减少。与未病变的猴子相比，经尼古丁治疗的病变猴子纹状体中 α 3/α 6 beta 2* 亚型的下降（使用 α-芋螺毒素 MII 敏感的 I-125-epibatidine 或 [125I] A85380 结合来定义）显着较小。使用 I-125-α-芋螺毒素 MII 鉴定的 α 3/α 6 beta 2* nAChR 未观察到这种差异。这些数据表明，在病变动物中，至少有两种纹状体 α 3/α 6 β 2* 亚型受到长期尼古丁治疗的不同影响。此外，结果显示纹状体 α 4 β 2* 和选择性 α 3/α 6 β 2* nAChR 亚型有所改善，结合之前的工作，证明长期尼古丁治疗可以恢复和/或防止黑质纹状体损伤后多种分子标记物的丢失。这些发现表明尼古丁或烟碱激动剂可能对帕金森病具有治疗价值。
Recent studies in nonhuman primates show that chronic nicotine treatment protects against nigrostriatal degeneration, with a partial restoration of neurochemical and functional measures in the striatum. The present studies were done to determine whether long-term nicotine treatment also protected against striatal nicotinic receptor (nAChR) losses after nigrostriatal damage. Monkeys were administered nicotine in the drinking water for 6 months and subsequently lesioned with the dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) over several months while nicotine was continued. I-125-Epibatidine, [I-125] 5-[I-125] iodo-3(2(S)-azetidinylmethoxy)pyridine (A85380), and I-125-alpha-conotoxinMII autoradiography was performed to evaluate changes in alpha 4 beta 2* and alpha 3/alpha 6 beta 2* nAChRs, the major striatal subtypes. Nicotine treatment increased alpha 4 beta 2* nAChRs by >= 50% in striatum of both unlesioned and lesioned animals. This increase in alpha 4 beta 2* nAChRs was significantly greater in lesioned compared with unlesioned monkey striatum. Chronic nicotine treatment led to a small decrease in alpha 3/alpha 6 beta 2* nAChR subtypes. The decline in alpha 3/alpha 6 beta 2* subtypes, defined using alpha-conotoxinMII-sensitive I-125-epibatidine or [125I] A85380 binding, was significantly smaller in striatum of nicotine-treated lesioned monkeys compared with unlesioned monkeys. This difference was not observed for alpha 3/alpha 6 beta 2* nAChRs identified using I-125-alpha-conotoxinMII. These data suggest that there are at least two striatal alpha 3/alpha 6 beta 2* subtypes that are differentially affected by chronic nicotine treatment in lesioned animals. In addition, the results showing an improvement in striatal alpha 4 beta 2* and select alpha 3/alpha 6 beta 2* nAChR subtypes, combined with previous work, demonstrate that chronic nicotine treatment restores and/or protects against the loss of multiple molecular markers after nigrostriatal damage. Such findings suggest that nicotine or nicotinic agonists may be of therapeutic value in Parkinson's disease.