Otto D, Unsicker K
Department of Anatomy and Cell Biology, University of Heidelberg, Germany.
Glia. 1994 May;11(1):47-56. doi: 10.1002/glia.440110107.
Fibroblast growth factor (FGF) is synthesized and stored by astroglial cells and regulates their proliferation and differentiation in vitro. Its implication in the transformation of quiescent astrocytes into reactive astroglia has been discussed. Using a mouse model of Parkinson's disease, in which FGF-2 has been shown to exert marked neuroprotection of nigrostriatal dopaminergic neurons, we have studied striatal levels of glial fibrillary acidic protein (GFAP), an established marker for astrocytes, and the distribution and morphologies of GFAP-immunoreactive cells following treatments with the neurotoxic drug 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), the growth factor FGF-2, and the non-trophic control protein cytochrome C (cyt C). Systemic injections of MPTP (30 mg/kg) on 3 consecutive days, which we have previously shown to cause profound and long-lasting damage to the nigrostriatal system, induced an approximate 20% transient increase in striatal GFAP, determined by enzyme-linked immunosorbent assay (ELISA), 1 day after the final MPTP injection (= day 4), with subsequent normalization at day 7, which lasted until the end of the experiment (day 18). Morphologically, MPTP elicited a marked increase in number, size, arborization, and stainability of GFAP-immunoreactive cells at day 4 in a striatal area adjacent to the corpus callosum, which was evaluated throughout all experiments. Even on day 18, astrocytes were still apparently larger and more branched than in unlesioned controls. Administration of 4 micrograms of either FGF-2 or cyt C (soaked into a piece of Gelfoam unilaterally to the right striatum in either MPTP- or saline-injected controls) increased striatal GFAP levels bilaterally about 2- to 2.5-fold at 14 days, when FGF-2 showed marked protection of dopaminergic parameters. Likewise, GFAP immunocytochemistry revealed increased numbers of intensely immunoreactive astrocytes under any experimental situation. Differences in the morphologies of astrocytes in FGF-2- and cyt C-treated animals were very subtle and only noted at greater distances away from the site of application of the factors. We conclude that FGF-2, a potent neurotrophic factor for the neurotoxically lesioned nigrostriatal system, does not cause a marked astrogliotic reaction, which might be expected from previous in vitro and in vivo studies in other neural systems. This may limit concerns regarding potential applicability of FGF-2 to the parkinsonian striatum.
成纤维细胞生长因子（FGF）由星形胶质细胞合成并储存，在体外可调节其增殖和分化。人们已讨论过它在静止星形胶质细胞向反应性星形胶质细胞转化过程中的作用。在帕金森病小鼠模型中，FGF-2已被证明对黑质纹状体多巴胺能神经元具有显著的神经保护作用，我们研究了胶质纤维酸性蛋白（GFAP）的纹状体水平（GFAP是一种已确定的星形胶质细胞标志物），以及在用神经毒性药物1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP）、生长因子FGF-2和非营养性对照蛋白细胞色素C（cyt C）处理后GFAP免疫反应性细胞的分布和形态。连续3天全身注射MPTP（30 mg/kg），我们之前已证明这会对黑质纹状体系统造成严重且持久的损伤，在最后一次MPTP注射后1天（即第4天），通过酶联免疫吸附测定（ELISA）确定纹状体GFAP出现约20%的短暂升高，随后在第7天恢复正常，并持续到实验结束（第18天）。从形态学上看，在整个实验过程中评估发现，MPTP在第4天使胼胝体附近纹状体区域中GFAP免疫反应性细胞的数量、大小、分支和染色性显著增加。即使在第18天，星形胶质细胞仍明显比未受损对照组的更大且分支更多。给予4微克FGF-2或cyt C（单侧浸泡在一片明胶海绵中，注入到MPTP或生理盐水注射对照组的右侧纹状体），在第14天时双侧纹状体GFAP水平升高约2至2.5倍，此时FGF-2对多巴胺能参数显示出显著的保护作用。同样，GFAP免疫细胞化学显示在任何实验情况下，强烈免疫反应性星形胶质细胞的数量都增加。FGF-2和cyt C处理动物的星形胶质细胞形态差异非常细微，仅在远离因子应用部位的较大距离处才观察到。我们得出结论，FGF-2作为一种对神经毒性损伤的黑质纹状体系统具有强大神经营养作用的因子，不会引起明显的星形胶质细胞增生反应，而在其他神经系统的先前体外和体内研究中可能会预期出现这种反应。这可能会减少对FGF-2应用于帕金森病纹状体潜在适用性的担忧。
