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通过纹状体内、黑质内和丘脑底核内多巴胺能移植增强偏侧帕金森病大鼠的感觉运动行为恢复。

Enhancement of sensorimotor behavioral recovery in hemiparkinsonian rats with intrastriatal, intranigral, and intrasubthalamic nucleus dopaminergic transplants.

作者信息

Mukhida K, Baker K A, Sadi D, Mendez I

机构信息

Neural Transplantation Laboratory, Departments of Anatomy and Neurobiology and Surgery (Division of Neurosurgery), Dalhousie University, Halifax, Nova Scotia, Canada B3H 4H7.

出版信息

J Neurosci. 2001 May 15;21(10):3521-30. doi: 10.1523/JNEUROSCI.21-10-03521.2001.

Abstract

One of the critical variables that influences the efficacy of clinical neural transplantation for Parkinson's disease (PD) is optimal graft placement. The current transplantation paradigm that focuses on ectopic placement of fetal grafts in the striatum (ST) fails to reconstruct the basal ganglia circuitry or normalize neuronal activity in important basal ganglia structures, such as the substantia nigra (SN) and the subthalamic nucleus (STN). The aim of this study was to investigate a multitarget neural transplantation strategy for PD by assessing whether simultaneous dopaminergic transplants in the ST, SN, and STN induce functional recovery in hemiparkinsonian rats. Forty-six female Wistar rats with unilateral 6-hydroxydopamine lesions of the nigrostriatal pathway were randomly divided into eight groups and received lesions only or injections of 900,000 embryonic rat ventral mesencephalic cells in the (1) ST, (2) SN, (3) STN, (4) ST and SN, (5) ST, SN, and STN, (6) ST and STN, or (7) SN and STN. The number of cells transplanted was equally divided among grafting sites. Animals with two grafts received 450,000 cells in each structure, and animals with three grafts received 300,000 cells per structure. Recovery was assessed by amphetamine-induced rotations and the stepping tests. Graft survival was assessed using tyrosine hydroxylase immunohistochemistry. At 8 weeks after transplantation, simultaneous dopaminergic transplants in the ST, SN, and STN induced significant improvement in rotational behavior and stepping test scores. Intrastriatal transplants were associated with significant recovery of rotational asymmetry, whereas SN and STN transplants were associated with improved forelimb function scores. These results suggest that restoration of dopaminergic activity to multiple basal ganglia targets, such as the ST and SN, or the ST and STN, promotes a more complete functional recovery of complex sensorimotor behaviors. A multitarget transplant strategy aimed at optimizing dopaminergic reinnervation of the basal ganglia may be crucial in improving clinical outcomes in PD patients.

摘要

影响帕金森病(PD)临床神经移植疗效的关键变量之一是最佳移植物植入位置。当前专注于将胎儿移植物异位植入纹状体(ST)的移植模式,无法重建基底神经节回路,也无法使重要基底神经节结构(如黑质(SN)和丘脑底核(STN))中的神经元活动正常化。本研究的目的是通过评估在ST、SN和STN同时进行多巴胺能移植是否能诱导偏侧帕金森大鼠的功能恢复,来探究一种针对PD的多靶点神经移植策略。46只单侧黑质纹状体通路6-羟基多巴胺损伤的雌性Wistar大鼠被随机分为八组,分别接受仅损伤处理,或在以下部位注射900,000个胚胎大鼠腹侧中脑细胞:(1)ST,(2)SN,(3)STN,(4)ST和SN,(5)ST、SN和STN,(6)ST和STN,或(7)SN和STN。移植的细胞数量在各个移植部位平均分配。接受两个移植物的动物在每个结构中植入450,000个细胞,接受三个移植物的动物在每个结构中植入300,000个细胞。通过苯丙胺诱导的旋转和步测试验评估恢复情况。使用酪氨酸羟化酶免疫组织化学评估移植物存活情况。移植后8周,在ST、SN和STN同时进行多巴胺能移植可显著改善旋转行为和步测试验评分。纹状体内移植与旋转不对称的显著恢复相关,而SN和STN移植与前肢功能评分的改善相关。这些结果表明,将多巴胺能活性恢复到多个基底神经节靶点,如ST和SN,或ST和STN,可促进复杂感觉运动行为更完全的功能恢复。旨在优化基底神经节多巴胺能再支配的多靶点移植策略可能对改善PD患者的临床结局至关重要。

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