Huang Luping Z, Parameswaran Neeraja, Bordia Tanuja, Michael McIntosh J, Quik Maryka
Basic Research Department, The Parkinson's Institute, Sunnyvale, California 94085, USA.
J Neurochem. 2009 May;109(3):826-37. doi: 10.1111/j.1471-4159.2009.06011.x. Epub 2009 Feb 24.
Nicotine reduces dopaminergic deficits in parkinsonian animals when administered before nigrostriatal damage. Here we tested whether nicotine is also beneficial when given to rats and monkeys with pre-existing nigrostriatal damage. Rats were administered nicotine before and after a unilateral 6-hydroxydopamine lesion of the medial forebrain bundle, and the results compared with those in which rats received nicotine only after lesioning. Nicotine pre-treatment attenuated behavioral deficits and lessened lesion-induced losses of the striatal dopamine transporter, and alpha6beta2* and alpha4beta2* nicotinic receptors (nAChRs). By contrast, nicotine administered 2 weeks after lesioning, when 6-hydroxydopamine-induced neurodegenerative effects are essentially complete, did not improve these same measures. Similar results were observed in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned monkeys. Nicotine did not enhance striatal markers when administered to monkeys with pre-existing nigrostriatal damage, in contrast to previous data that showed improvements when nicotine was given to monkeys before lesioning. These combined findings in two animal models suggest that nicotine is neuroprotective rather than neurorestorative against nigrostriatal damage. Receptor studies with (125)I-alpha-conotoxinMII and the alpha-conotoxinMII analog E11A were next performed to determine whether nicotine treatment pre- or post-lesioning differentially affected expression of alpha6alpha4beta2* and alpha6(nonalpha4)beta2* nAChR subtypes in striatum. The observations suggest that protection against nigrostriatal damage may be linked to striatal alpha6alpha4beta2* nAChRs.
在黑质纹状体损伤之前给予尼古丁，可减轻帕金森病动物的多巴胺能缺陷。在此，我们测试了对于已经存在黑质纹状体损伤的大鼠和猴子，给予尼古丁是否也有益处。在内侧前脑束单侧6-羟基多巴胺损伤前后给大鼠施用尼古丁，并将结果与仅在损伤后给予尼古丁的大鼠进行比较。尼古丁预处理减轻了行为缺陷，并减少了损伤诱导的纹状体多巴胺转运体、α6β2和α4β2烟碱型受体（nAChRs）的损失。相比之下，在损伤后2周给予尼古丁（此时6-羟基多巴胺诱导的神经退行性效应基本完成），并没有改善这些指标。在1-甲基-4-苯基-1,2,3,6-四氢吡啶损伤的猴子中也观察到了类似的结果。与之前在猴子损伤前给予尼古丁显示出改善的数据相反，当给予已经存在黑质纹状体损伤的猴子尼古丁时，并没有增强纹状体标记物。这两个动物模型的综合研究结果表明，尼古丁对黑质纹状体损伤具有神经保护作用而非神经修复作用。接下来进行了用（125）I-α-芋螺毒素MII和α-芋螺毒素MII类似物E11A的受体研究，以确定损伤前或损伤后给予尼古丁是否对纹状体中α6α4β2和α6（非α4）β2 nAChR亚型的表达有不同影响。这些观察结果表明，对黑质纹状体损伤的保护作用可能与纹状体α6α4β2* nAChRs有关。
