Kordower J H, Chen E Y, Mufson E J, Winn S R, Emerich D F
Department of Neurological Sciences, Rush Presbyterian Medical Center, Chicago, IL 60612, USA.
Neuroscience. 1996 May;72(1):63-77. doi: 10.1016/0306-4522(95)00543-9.
Nerve growth factor selectively prevents the degeneration of cholinergic neurons following intrastriatal infusion but rescues both cholinergic and noncholinergic striatal neurons if the nerve growth factor is secreted from grafts of genetically modified fibroblasts. The present study evaluated whether grafted fibroblasts genetically modified to secrete human nerve growth factor could provide trophic influences upon intact cholinergic and noncholinergic striatal neurons. Unilateral striatal grafts of polymer-encapsulated cells genetically modified to secrete human nerve growth factor induced hypertrophy and significantly increased the optical density of choline acetyltransferase-immunoreactive striatal neurons one, two, and four weeks post-transplantation relative to rats receiving identical grafts missing only the human nerve growth factor construct. Nerve growth factor secreting grafts also induced a hypertrophy of noncholinergic neuropeptide Y-immunoreactive striatal neurons one, two, and four weeks post-transplantation. Glutamic acid decarboxylase-immunoreactive neurons were unaffected by the human nerve growth factors secreting grafts. The effects upon choline acetyltransferase-immunoreactive and neuropeptide Y-immunoreactive striatal neurons dissipated following retrieval of the implants. Immunocytochemistry for nerve growth factor revealed intense graft-derived immunoreactivity for up to 1000 microns from the capsule extending along the dorsoventral axis of the striatum. Nerve growth factor-immunoreactivity was also observed within a subpopulation of striatal neurons and may represent nerve growth factor consumer neurons which retrogradely transported graft-derived nerve growth factor. When explanted, grafts produced 2-4 ng human nerve growth factor/24 h over the time course of this study indicating that this level of continuous human nerve growth factor secretion was sufficient to mediate the effects presently observed.
神经生长因子在纹状体内注入后可选择性地防止胆碱能神经元变性，但如果神经生长因子由基因修饰的成纤维细胞移植体分泌，则可挽救胆碱能和非胆碱能纹状体神经元。本研究评估了经基因修饰以分泌人神经生长因子的移植成纤维细胞是否能对完整的胆碱能和非胆碱能纹状体神经元产生营养作用。与仅接受缺少人神经生长因子构建体的相同移植体的大鼠相比，经基因修饰以分泌人神经生长因子的聚合物包裹细胞的单侧纹状体移植在移植后1周、2周和4周诱导了肥大，并显著增加了胆碱乙酰转移酶免疫反应性纹状体神经元的光密度。分泌神经生长因子的移植体在移植后1周、2周和4周也诱导了非胆碱能神经肽Y免疫反应性纹状体神经元的肥大。谷氨酸脱羧酶免疫反应性神经元不受分泌人神经生长因子的移植体影响。取出植入物后，对胆碱乙酰转移酶免疫反应性和神经肽Y免疫反应性纹状体神经元的影响消失。神经生长因子的免疫细胞化学显示，从囊膜沿纹状体的背腹轴延伸多达1000微米的范围内有强烈的移植体来源的免疫反应性。在纹状体神经元的一个亚群中也观察到神经生长因子免疫反应性，这可能代表逆向转运移植体来源神经生长因子的神经生长因子消耗性神经元。在本研究的时间过程中，当移植体被移出时，其产生2 - 4纳克人神经生长因子/24小时，表明这种持续的人神经生长因子分泌水平足以介导目前观察到的效应。
