Rosenblad C, Kirik D, Devaux B, Moffat B, Phillips H S, Björklund A
Department of Physiology and Neuroscience, Wallenberg Neuroscience Center, Lund University, Sweden.
Eur J Neurosci. 1999 May;11(5):1554-66. doi: 10.1046/j.1460-9568.1999.00566.x.
Both glial cell line-derived neurotrophic factor (GDNF) and its recently discovered congener, neurturin (NTN), have been shown to exert neuroprotective effects on lesioned nigral dopamine (DA) neurons when administered at the level of the substantia nigra. In the present study, we have explored the relative in vivo potency of these two neurotrophic factors using two alternative routes of administration, into the striatum or the lateral ventricle, which may be more relevant in a clinical setting. In rats subjected to an intrastriatal (IS) 6-hydroxydopamine (6-OHDA) lesion, GDNF and NTN were injected every third day for 3 weeks starting on the day after the 6-OHDA injection. GDNF provided almost complete (90-92%) protection of the lesioned nigral DA neurons after both IS and intracerebroventricular (ICV) administration. NTN, by contrast, was only partially effective after IS injection (72% sparing) and totally ineffective after ICV injection. Although the trophic factor injections protected the nigral neurons from lesion-induced cell death, the level of expression of the phenotypic marker, tyrosine hydroxylase (TH), was markedly reduced in the rescued cell bodies. The extent of 6-OHDA-induced DA denervation in the striatum was unaffected by both types of treatment; consistent with this observation, the high rate of amphetamine-induced turning seen in the lesioned control animals was unaltered by either GDNF or NTN treatment. In the GDNF-treated animals, and to a lesser extent also after IS NTN treatment, prominent axonal sprouting was observed within the globus pallidus, at the level where the lesioned nigrostriatal axons are known to end at the time of onset of the neurotrophic factor treatment. The results show that GDNF is highly effective as a neuroprotective and axon growth-stimulating agent in the IS 6-OHDA lesion model after both IS and ICV administration. The lower efficacy of NTN after IS, and particularly ICV, administration may be explained by the poor solubility and diffusion properties at neutral pH.
胶质细胞源性神经营养因子（GDNF）及其最近发现的同源物神经营养素（NTN），已被证明当在黑质水平给药时，对受损的黑质多巴胺（DA）神经元具有神经保护作用。在本研究中，我们使用两种不同的给药途径，即纹状体或侧脑室给药，探讨了这两种神经营养因子在体内的相对效力，这两种途径在临床环境中可能更具相关性。在接受纹状体内（IS）6-羟基多巴胺（6-OHDA）损伤的大鼠中，从6-OHDA注射后的第二天开始，每隔一天注射一次GDNF和NTN，持续3周。在IS和脑室内（ICV）给药后，GDNF对受损的黑质DA神经元提供了几乎完全（90-92%）的保护。相比之下，NTN在IS注射后仅部分有效（保留72%），在ICV注射后完全无效。尽管注射营养因子可保护黑质神经元免受损伤诱导的细胞死亡，但在获救的细胞体中，表型标记物酪氨酸羟化酶（TH）的表达水平明显降低。两种治疗方法均未影响纹状体中6-OHDA诱导的DA去神经支配程度；与此观察结果一致，受损对照动物中高频率的苯丙胺诱导的旋转不受GDNF或NTN治疗的影响。在GDNF治疗的动物中，以及在较小程度上，在IS NTN治疗后，在苍白球内观察到明显的轴突发芽，在神经营养因子治疗开始时，受损的黑质纹状体轴突已知在此处终止。结果表明，在IS 6-OHDA损伤模型中，GDNF在IS和ICV给药后作为神经保护剂和轴突生长刺激剂都非常有效。NTN在IS给药后，尤其是ICV给药后效力较低，这可能是由于其在中性pH下的溶解性和扩散性较差所致。
