Restoration of dopamine transporter density in the striatum of fetal ventral mesencephalon-grafted, but not sham-grafted, MPTP-treated Parkinsonian monkeys
Restoration of dopamine transporter density in the striatum of fetal ventral mesencephalon-grafted, but not sham-grafted, MPTP-treated Parkinsonian monkeys
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DOI：
10.1016/0963-6897(95)02034-9
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发表时间：
1996-03-01
影响因子：
3.3
通讯作者：
Roth, RH
中科院分区：
文献类型：
--
作者：
Elsworth, JD;Brittan, MS;Roth, RH
将胎儿多巴胺神经元移植到成年纹状体可能提供了一种逆转纹状体多巴胺缺乏的方法，这种缺陷是帕金森氏病的特征。许多对啮齿动物的研究支持了神经移植可能是治疗帕金森氏症的有效方法。然而，临床研究通常在运动异常方面比在低等物种中观察到的改善更温和。移植后存活的胎儿多巴胺神经元的数量可能不足以将巨大的人类纹状体的多巴胺能神经支配恢复到显著恢复的水平。事实上，还没有关于移植物生长的定量研究来表明目前的技术可以重新支配多巴胺耗竭的纹状体的哪一部分，此外，本研究以9只1-甲基-4-苯基-1，2，3，6-四氢吡啶(MPTP)治疗的帕金森病猴为研究对象，对这些问题进行了研究。结果表明，植入MPTP的猕猴纹状体中的多巴胺转运体密度(用放射自显影定量测量)或组织多巴胺浓度(用高效液相色谱法测量)都没有增加，在假移植和未植入MPTP的猕猴中，纹状体中的多巴胺浓度降低了99%。根据对每只猴尾状核和壳核16个取样点的分析，假移植组和未植入MPTP组的行为没有恢复，相反，将胚胎多巴胺神经元移植到尾状核或壳核可以显著提高移植的纹状核多巴胺转运体密度和多巴胺水平。将供体腹侧中脑平均分割并植入尾状核或壳核的6个部位，每只猴的一个移植部位进行多巴胺转运体放射自显影检查，在有移植纤维的切片上，平均1/3的移植核体积被高密度的多巴胺转运体占据，这种增加的多巴胺转运体密度被定义为至少是对照密度的5-10%。然而，在移植MPTP治疗的组中没有观察到完全的行为恢复，这些数据不支持宿主多巴胺系统的再生是对严重帕金森病猴子的假植入程序的反应的假说。目前的研究阐明了描述宿主多巴胺耗竭水平、移植物诱导的多巴胺能恢复程度和行为恢复之间关系的应用技术的力量。
Transplantation of fetal dopamine neurons to the adult striatum potentially offers a means to reverse the striatal dopamine deficiency that characterizes Parkinson's disease, Many investigations in rodents have supported the hope that neural grafting may be a useful treatment for parkinsonism, However, clinical studies have generally produced more modest improvements in motor abnormalities than observed in lower species, It is possible that the number of fetal dopamine neurons that survive transplantation is insufficient to restore dopaminergic innervation of the large human striatum to a level where striking recovery is obtained, In fact, there has been no quantitative study of graft outgrowth to indicate what portion of the dopamine-depleted striatum might be reinnervated with present techniques, Furthermore, it has been speculated that regeneration of the host dopamine system in response to the implantation surgery may play an important role in the beneficial effects of neural grafting in primates, The present study used nine 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) treated parkinsonian monkeys to investigate these issues, Sham implantation procedures produced no increase in either dopamine transporter density (measured by quantitative autoradiography) or tissue dopamine concentration (measured by HPLC) in the striatum of MPTP-treated monkeys, In sham-grafted and nonimplanted MPTP-treated monkeys, the striatal dopamine concentration was reduced by 99%, based on analysis of 16 sampled sites in the caudate nucleus and putamen of each monkey, No behavioral recovery was seen in the sham-grafted and nonimplanted MPTP-treated groups, In contrast, transplantation of fetal dopamine neurons to the caudate nucleus or putamen of MPTP-treated monkeys resulted in a significant elevation of dopamine transporter density and dopamine levels in the grafted striatal nucleus, Each grafted MPTP-treated monkey received ventral mesencephalon dopamine neurons from one donor harvested during putative neurogenesis. Donor ventral mesencephalon was divided equally and implanted into six sites either in the caudate nucleus or putamen, One graft site in each monkey was examined by dopamine transporter autoradiography, In sections in which graft fibers were present, a mean of one-third of the volume of the grafted nucleus was occupied by an elevated density of dopamine transporters, This increase in dopamine transporter density was defined to be at least 5-10% of the control density. However, full behavioral recovery was not observed in the grafted MPTP-treated group, These data provide no support for the hypothesis that regeneration of the host dopamine system occurs in response to a sham implantation procedure in severely parkinsonian monkeys. The current study illustrates the power of the applied techniques for delineating the relationship between the level of host dopamine depletion, the extent of graft-induced dopaminergic restoration, and behavioral recovery.