Gash D M, Zhang Z, Cass W A, Ovadia A, Simmerman L, Martin D, Russell D, Collins F, Hoffer B J, Gerhardt G A
Department of Anatomy and Neurobiology, University of Kentucky, Lexington 40536, USA.
J Comp Neurol. 1995 Dec 18;363(3):345-58. doi: 10.1002/cne.903630302.
Effects of a single injection of either 150 micrograms human recombinant glial cell line-derived neurotrophic factor (rGDNF) or vehicle into the right substantia nigra were analyzed in 12 normal adult female rhesus monkeys. The studies included evaluating whole animal behavior, electrochemical recordings of striatal dopamine release, neurochemical determinations of basal ganglia and nigral monoamine levels, and immunohistochemical staining of the nigrostriatal dopamine system. The behavioral effects over the 3-week observation period following trophic factor administration were small, with blinded observers unable to distinguish between GDNF- and vehicle-treated animals. Quantitative measurements did show that five of six trophic factor recipients experienced some weight loss and four of the six GDNF recipients displayed small, but significant, increases in daytime activity levels. In vivo electrochemical recordings in the ipsilateral caudate and putamen 3 weeks after GDNF administration revealed increased potassium-evoked release of dopamine in trophic factor recipients. In a second series of animals killed at the same time, dopamine levels in the substantia nigra and ventral tegmental area of GDNF recipients were significantly increased, with ipsilateral values more than 200% higher than contralateral and control levels. Levels of the dopamine metabolite HVA were significantly elevated in the substantia nigra, ventral tegmental area, and caudate nucleus ipsilateral to the trophic factor injection. There was a trend toward increased HVA levels in the ipsilateral putamen, nucleus accumbens, and globus pallidus in GDNF-treated animals, but the ratios of HVA to dopamine were not significantly different between vehicle- and GDNF-treated recipients. Although some tissue damage from the delivery of concentrated trophic factor was evident, dopamine neurons remained in an adjacent to the injection site. In the substantia nigra ipsilateral to GDNF administration, dopamine-neuron perikaryal size was significantly increased, along with a significant increase in tyrosine hydroxylase-positive axons and dendrites. We conclude that, in the adult rhesus monkey, a single intranigral GDNF injection induces a significant upregulation of mesencephalic dopamine neurons which lasts for weeks.
在12只正常成年雌性恒河猴中，分析了向右侧黑质单次注射150微克人重组胶质细胞源性神经营养因子（rGDNF）或赋形剂的效果。研究包括评估全动物行为、纹状体多巴胺释放的电化学记录、基底神经节和黑质单胺水平的神经化学测定以及黑质纹状体多巴胺系统的免疫组织化学染色。在给予营养因子后的3周观察期内，行为影响较小，盲法观察者无法区分GDNF治疗组和赋形剂治疗组的动物。定量测量确实显示，六只营养因子接受者中有五只出现了一些体重减轻，六只GDNF接受者中有四只白天活动水平有小幅但显著的增加。在给予GDNF 3周后，对同侧尾状核和壳核进行的体内电化学记录显示，营养因子接受者中钾诱发的多巴胺释放增加。在同时处死的第二组动物中，GDNF接受者黑质和腹侧被盖区的多巴胺水平显著升高，同侧值比 contralateral和对照水平高出200%以上。在营养因子注射同侧的黑质、腹侧被盖区和尾状核中，多巴胺代谢物HVA的水平显著升高。在GDNF治疗的动物中，同侧壳核、伏隔核和苍白球中的HVA水平有升高趋势，但赋形剂治疗组和GDNF治疗组接受者之间HVA与多巴胺的比率没有显著差异。尽管从浓缩营养因子的递送中明显可见一些组织损伤，但多巴胺神经元仍留在注射部位附近。在GDNF给药同侧的黑质中，多巴胺神经元胞体大小显著增加，酪氨酸羟化酶阳性轴突和树突也显著增加。我们得出结论，在成年恒河猴中，单次黑质内注射GDNF可诱导中脑多巴胺神经元显著上调，这种上调可持续数周。
