Granholm A C, Mott J L, Bowenkamp K, Eken S, Henry S, Hoffer B J, Lapchak P A, Palmer M R, van Horne C, Gerhardt G A
Department of Basic Science, University of Colorado Health Sciences Center, Denver 80262, USA.
Exp Brain Res. 1997 Aug;116(1):29-38. doi: 10.1007/pl00005741.
One approach to replace lost dopaminergic neurons in Parkinson's disease is to transplant fetal mesencephalic tissue into the striatum. In an attempt to expand the developmental window useful for grafting of mesencephalic tissue and increase the fiber outgrowth from grafted dopaminergic neurons, we have pretreated fetal mesencephalic tissue with the dopaminotrophic factor glial cell line-derived neurotrophic factor (GDNF). Mesencephalic tissue pieces from embryonic day 18-19 Fischer 344 rats were preincubated for 20 min with GDNF (1 microg/microl) or vehicle. Two tissue pieces were then transplanted into the striatum of rats that had been unilaterally lesioned by medial forebrain bundle injections of 6-hydroxydopamine. The animals were tested for apomorphine-induced rotations prior to intracranial grafting. Host rats received intrastriatal injections of 10 microg GDNF or control solution at 10 days and 4 weeks postgrafting. The animals were tested in the rotometer twice monthly following transplantation. Despite the fact that these transplants were from a suboptimal donor stage, the rotations were significantly decreased in both transplanted groups. Immunohistochemical evaluation of the host brains revealed that the overall size of transplanted mesencephalic tissue was significantly increased in the GDNF-treated animals, and that the average size of transplanted tyrosine hydroxylase (TH)-positive neurons was also increased. Furthermore, we found that the innervation density of surrounding host striatal tissue was significantly increased in the GDNF-treated group, as compared with controls. Taken together, these results suggest that treatment of intrastriatal ventral mesencephalon grafts with GDNF can optimize the conditions for intracranial grafting and thus improve the chances for functional recovery following the intrastriatal grafting procedure.
在帕金森病中，一种替代丢失的多巴胺能神经元的方法是将胎儿中脑组织移植到纹状体中。为了扩大对中脑组织移植有用的发育窗口，并增加移植的多巴胺能神经元的纤维生长，我们用多巴胺营养因子胶质细胞系衍生神经营养因子（GDNF）对胎儿中脑组织进行了预处理。将来自胚胎第18 - 19天的Fischer 344大鼠的中脑组织块与GDNF（1微克/微升）或赋形剂预孵育20分钟。然后将两块组织移植到通过内侧前脑束注射6 - 羟基多巴胺单侧损伤的大鼠纹状体中。在颅内移植前对动物进行阿扑吗啡诱导的旋转测试。宿主大鼠在移植后10天和4周接受纹状体内注射10微克GDNF或对照溶液。移植后每月两次在旋转测试仪中对动物进行测试。尽管这些移植来自次优的供体阶段，但两个移植组的旋转次数均显著减少。对宿主大脑的免疫组织化学评估显示，在GDNF处理的动物中，移植的中脑组织的总体积显著增加，并且移植的酪氨酸羟化酶（TH）阳性神经元的平均大小也增加。此外，我们发现与对照组相比，GDNF处理组周围宿主纹状体组织的神经支配密度显著增加。综上所述，这些结果表明用GDNF处理纹状体内腹侧中脑移植物可以优化颅内移植的条件，从而提高纹状体内移植手术后功能恢复的机会。
