Abin-Carriquiry J Andrés, McGregor-Armas Ronald, Costa Gustavo, Urbanavicius Jessika, Dajas Federico
Instituto de Investigaciones Biológicas Clemente Estable, Department of Neurochemistry, Avda Italia 3318, 11600 Montevideo, Uruguay.
Neurotox Res. 2002 Mar;4(2):133-9. doi: 10.1080/10298420290015863.
While nicotine, through stimulation of a specific sub-population of nicotinic acetylcholine receptors (nAChR) appears to protect cells in culture against a variety of insults, studies in vivo show controversial results. In a previous paper we have shown that in the 6-hydroxydopamine (6-OHDA) model of experimental parkinsonism, an intermittent administration schedule of nicotine (4 h before and 20, 44 and 68 h after 6-OHDA) was able to prevent the decrease of dopamine (DA) concentration in the corpus striatum (CS) provoked by the partial lesion of the substantia nigra (50% neuronal death after 6 micro g of 6-OHDA). To further analyze the mechanisms of nicotine effects, we performed a microdialysis study of striatal extracellular DA concentrations utilizing the nicotine administration schedule that was able to prevent DA decrease. Basal extracellular DA concentrations in the CS were maintained after 6-OHDA and were not modified by nicotine. Basal DOPAC levels were decreased after the neurotoxic administration. The response of extracellular DA to potassium chloride (KCl) challenge was significantly lower after 6-OHDA than in control animals. Nicotine significantly reversed this decrease. As previous studies have shown, the striatal DA terminals surviving the 6-OHDA toxic effect are able to keep extracellular DA concentrations close to normal, likely increasing DA synthesis. Nevertheless, the application of a releasing factor such as KCl shows the fragility of this equilibrium, exposing a decrease in the terminal number. Nicotine, through a further activation of tyrosine hydroxylase and DA synthesis or by prolonging the life of DA terminals, could reverse the effect of 6-OHDA.
虽然尼古丁通过刺激特定亚群的烟碱型乙酰胆碱受体（nAChR）似乎能保护培养中的细胞免受多种损伤，但体内研究显示出有争议的结果。在之前的一篇论文中，我们已经表明，在实验性帕金森病的6-羟基多巴胺（6-OHDA）模型中，尼古丁的间歇性给药方案（在6-OHDA之前4小时以及之后20、44和68小时）能够预防黑质部分损伤（6微克6-OHDA后50%神经元死亡）所引发的纹状体（CS）中多巴胺（DA）浓度的降低。为了进一步分析尼古丁作用的机制，我们利用能够预防DA降低的尼古丁给药方案，对纹状体细胞外DA浓度进行了微透析研究。6-OHDA后CS中的基础细胞外DA浓度得以维持，且未被尼古丁改变。神经毒性给药后基础3,4-二羟基苯乙酸（DOPAC）水平降低。6-OHDA后细胞外DA对氯化钾（KCl）刺激的反应明显低于对照动物。尼古丁显著逆转了这种降低。如先前研究所示，在6-OHDA毒性作用后存活的纹状体DA终末能够使细胞外DA浓度接近正常，可能是通过增加DA合成。然而，应用诸如KCl这样的释放因子显示出这种平衡的脆弱性，表明终末数量减少。尼古丁可能通过进一步激活酪氨酸羟化酶和DA合成，或通过延长DA终末的寿命，来逆转6-OHDA的作用。
