Barc Stéphanie, Page Guylène, Barrier Laurence, Garreau Lucette, Guilloteau Denis, Fauconneau Bernard, Chalon Sylvie
Groupe d'Etudes des Mécanismes Cellulaires de l'Ischémie GEMCI, EA 1223, Poitiers, France.
J Neurochem. 2002 Feb;80(3):365-74. doi: 10.1046/j.0022-3042.2001.00743.x.
Many striatal dopaminergic markers are available for estimating the degree of the nigrostriatal lesion by MPTP/MPP+, but the changes of these markers are not perfectly matched. In this study we investigated different striatal markers and determined which ones closely reflected the nigrostriatal alteration. The in vivo binding of (E)-N-(3-iodoprop-2-enyl)-2-beta-carbomethoxy-3beta-(4'-methylphenyl)nortropane (PE2I), a selective and potent inhibitor of the neuronal dopamine transporter (DAT) was considered as the reference index of injury of striatal dopaminergic nerve-endings. Rats received a 10-microg MPP+ injection in the right substantia nigra and were killed at 7 days after lesion. The results were as follows: (i) a decrease (66%) of the biodistribution of [125I]PE2I; (ii) a great reduction of the DAT expression measured by the binding of [125I]PE2I in striatal membranes (Bmax decreased by 54%) and in cerebral slices (88%); (iii) an 80% inhibition of the vesicular monoamine transporter expression revealed by the binding of [3H]dihydrotetrabenazine in cerebral slices; (iv) a robust decrease in the quantity of DA and its metabolites (about 50-60%); (v) a slight modification of the DAT activity with a decreased number of functional sites (Vmax decreased by 12%, p < 0.05) without change of the affinity in striatal synaptosomes. Among these markers the binding of [125I]PE2I in membrane homogenates and the content of DA, and its metabolites, in striatum could be the most relevant in vitro indexes of the degenerative state of the nigrostriatal pathway after MPP+ lesion.
许多纹状体多巴胺能标记物可用于通过MPTP/MPP⁺评估黑质纹状体损伤的程度，但这些标记物的变化并不完全匹配。在本研究中，我们调查了不同的纹状体标记物，并确定了哪些标记物能密切反映黑质纹状体的改变。（E）-N-（3-碘丙-2-烯基）-2-β-甲氧羰基-3β-（4'-甲基苯基）去甲托烷（PE2I）是一种选择性且强效的神经元多巴胺转运体（DAT）抑制剂，其体内结合被视为纹状体多巴胺能神经末梢损伤的参考指标。大鼠右侧黑质接受10μg MPP⁺注射，并在损伤后7天处死。结果如下：（i）[¹²⁵I]PE2I的生物分布减少（66%）；（ii）通过[¹²⁵I]PE2I与纹状体膜（Bmax降低54%）和脑片（88%）结合测定的DAT表达大幅降低；（iii）通过[³H]二氢丁苯那嗪与脑片结合显示囊泡单胺转运体表达受到80%的抑制；（iv）多巴胺及其代谢产物的量显著减少（约50 - 60%）；（v）DAT活性有轻微改变，功能位点数量减少（Vmax降低12%，p < 0.05），而纹状体突触体中的亲和力无变化。在这些标记物中，膜匀浆中[¹²⁵I]PE2I的结合以及纹状体中多巴胺及其代谢产物的含量可能是MPP⁺损伤后黑质纹状体通路退变状态最相关的体外指标。
