Preservation of a functional nigrostriatal dopamine pathway by GDNF in the intrastriatal 6-OHDA lesion model depends on the site of administration of the trophic factor
Preservation of a functional nigrostriatal dopamine pathway by GDNF in the intrastriatal 6-OHDA lesion model depends on the site of administration of the trophic factor
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DOI：
10.1046/j.1460-9568.2000.00274.x
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发表时间：
2000-11-01
影响因子：
3.4
通讯作者：
Björklund, A
中科院分区：
文献类型：
--
作者：
Kirik, D;Rosenblad, C;Björklund, A
在这里，我们研究了胶质细胞源性神经营养因子（GDNF），作为一个单一的团注前，纹状体内6-羟基多巴胺（6-OHDA）的病变，可以保护黑质纹状体多巴胺神经元对毒素诱导的损伤，并保持正常的运动功能在受损的动物。在6-OHDA损伤（20 μ g/3穆尔）之前6小时，在纹状体（25 μ g）、黑质（25 μ g）或侧脑室（50 μ g）中注射GDNF或赋形剂。通过步进和药物诱导的运动不对称试验评价运动功能。单独给予载体的损伤动物显示出对安非他明的反应的明显同侧偏向（13转/分钟），对阿扑吗啡的中度对侧偏向（4.5转/分钟）和对侧前爪的中度至重度步进缺陷（3至4步，与未受损侧的11-13步相比）。将GDNF注射到纹状体中对黑质纹状体功能（旋转测试中为1-2转/分钟，踏步测试中为7 - 8步）和黑质纹状体通路的完整性都具有显著的保护作用，这被视为对黑质中的细胞体和纹状体中的多巴胺神经支配的保护。在黑质中注射GDNF对黑质细胞体有保护作用，但对纹状体神经支配没有保护作用，并且未能提供任何功能益处。相比之下，黑质内GDNF对纹状体TH阳性纤维密度和药物诱导的旋转测试都有有害影响。脑室内注射没有效果。我们的结论是，在纹状体内6-OHDA损伤模型的正常运动功能的保存需要保护纹状体末端神经支配，这可以通过纹状体内，但不是黑质或脑室内，GDNF管理。
Here we studied whether glial cell line-derived neurotrophic factor (GDNF), given as a single bolus injection before an intrastriatal 6-hydroxydopamine (6-OHDA) lesion, can protect the nigrostriatal dopamine neurons against the toxin-induced damage and preserve normal motor functions in the lesioned animals. GDNF or vehicle was injected in the striatum (25 mug), substantia nigra (25 mug) or lateral ventricle (50 mug) 6 h before the 6-OHDA lesion (20 mug/3 muL). Motor function was evaluated by the stepping and drug-induced motor asymmetry tests. Lesioned animals given vehicle alone showed a clear ipsilateral-side bias in response to amphetamine (13 turns/min), a moderate contralateral-side bias to apomorphine (4.5 turns/min) and a moderate to severe stepping deficit on the contralateral forepaw (three to four steps, as compared with 11-13 steps on the unimpaired side). Injection of GDNF into the striatum had a significant protective effect both on nigrostriatal function (1-2 turns/min in the rotation tests and seven to eight steps in the stepping test), and the integrity of the nigrostriatal pathway, seen as a protection of both the cell bodies in the substantia nigra and the dopamine innervation in the striatum. Injection of GDNF in the nigra had a protective effect on the nigral cell bodies, but not the striatal innervation, and failed to provide any functional benefit. In contrast, intranigral GDNF had deleterious effects on both the striatal TH-positive fibre density and on drug-induced rotation tests. Intraventricular injection had no effect. We conclude that preservation of normal motor functions in the intrastriatal 6-OHDA lesion model requires protection of striatal terminal innervation, and that this can be achieved by intrastriatal, but not nigral or intraventricular, administration of GDNF.