Wang J, Bankiewicz K S, Plunkett R J, Oldfield E H
CNS Implantation and Regeneration Unit, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland.
J Neurosurg. 1994 Mar;80(3):484-90. doi: 10.3171/jns.1994.80.3.0484.
Intrastriatal implantation with dopaminergic of nondopaminergic tissue can elicit behavioral recovery in parkinsonian animals. Because in these animals, especially in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned monkeys, there are still considerable numbers of dopaminergic neurons left in the mesencephalon, implantation-induced trophic effects on host residual dopaminergic neurons have been suggested as a mechanism underlying the behavioral recovery. Gliosis around the graft is a universal finding in any implantation procedure and is probably mediated by interleukin-1 (IL-1); in addition, activated astrocytes secrete several neurotrophic factors in vitro. Therefore, the authors postulated that trophic effects from IL-1-induced gliosis may be a "final common pathway" for recovery in parkinsonian animals after implantation. Hemiparkinsonism was induced in rats by injection of 6-hydroxydopamine either directly into the substantia nigra or into the median forebrain bundle. The substantia nigra-lesioned rats showed complete depletion of dopaminergic neurons in the substantia nigra but sparing of those in the ventral tegmental area, whereas the median forebrain bundle-lesioned animals had depletion of dopaminergic cells in the substantia nigra and the ventral tegmental area. Polymer pellets containing either slow-released IL-1 alpha and beta or placebo pellets were implanted in the caudate nucleus on the lesioned side in both groups. The rats' rotational response to amphetamine was tested weekly for 8 weeks. Selective substantia nigra-lesioned rats with implantation of IL-1 pellets had a 45% reduction in amphetamine-induced rotation, whereas placebo-implanted substantia nigra-lesioned rats had a 14% reduction in rotation. In the median forebrain bundle-lesioned group, neither IL-1 nor placebo implantation elicited any effect on turning. Immunohistochemical staining for glial fibrillary acidic protein was markedly increased surrounding the IL-1 pellets compared to the placebo pellets. In the selective substantia nigra-lesioned rats with IL-1 pellets implanted in the caudate nucleus, a considerable number of tyrosine hydroxylase immunoreactive (TH-IR) fibers were observed in the medial and middle portions of the caudate nucleus. Fewer TH-IR fibers were seen in the rats with placebo-bearing pellets. These results suggest that neurotrophic activities mediated by IL-1 and reactive astrocytes might be a common path through which tissue trauma and some tissue transplants exert their beneficial effects in parkinsonian animals. Furthermore, most of the sprouted dopaminergic fibers induced by IL-1 in the caudate nucleus come from dopaminergic neurons in the ventral tegmental area.
向纹状体内植入多巴胺能或非多巴胺能组织可使帕金森病动物的行为恢复。因为在这些动物中，尤其是在1-甲基-4-苯基-1,2,3,6-四氢吡啶损伤的猴子中，中脑仍残留相当数量的多巴胺能神经元，植入诱导的对宿主残留多巴胺能神经元的营养作用被认为是行为恢复的潜在机制。移植周围的胶质细胞增生是任何植入手术中普遍存在的现象，可能由白细胞介素-1（IL-1）介导；此外，活化的星形胶质细胞在体外分泌多种神经营养因子。因此，作者推测IL-1诱导的胶质细胞增生产生的营养作用可能是帕金森病动物植入后恢复的“最终共同途径”。通过将6-羟基多巴胺直接注射到黑质或中脑前束来诱导大鼠偏侧帕金森病。黑质损伤的大鼠黑质中的多巴胺能神经元完全缺失，但腹侧被盖区的神经元保留，而中脑前束损伤的动物黑质和腹侧被盖区的多巴胺能细胞均缺失。两组动物在损伤侧的尾状核中植入含有缓释IL-1α和β的聚合物微丸或安慰剂微丸。每周对大鼠对苯丙胺的旋转反应进行8周测试。植入IL-1微丸的选择性黑质损伤大鼠对苯丙胺诱导的旋转减少了45%，而植入安慰剂的黑质损伤大鼠旋转减少了14%。在中脑前束损伤组中，植入IL-1或安慰剂均未对旋转产生任何影响。与安慰剂微丸相比，IL-1微丸周围的胶质纤维酸性蛋白免疫组化染色明显增加。在尾状核中植入IL-1微丸的选择性黑质损伤大鼠中，在尾状核的内侧和中部观察到相当数量的酪氨酸羟化酶免疫反应性（TH-IR）纤维。植入含安慰剂微丸的大鼠中观察到的TH-IR纤维较少。这些结果表明，IL-1和反应性星形胶质细胞介导的神经营养活性可能是组织损伤和一些组织移植在帕金森病动物中发挥有益作用的共同途径。此外，IL-1在尾状核中诱导的大多数新生多巴胺能纤维来自腹侧被盖区的多巴胺能神经元。
