Chadi G, Møller A, Rosén L, Janson A M, Agnati L A, Goldstein M, Ogren S O, Pettersson R F, Fuxe K
Department of Histology and Neurobiology, Karolinska Institute, Stockholm, Sweden.
Exp Brain Res. 1993;97(1):145-58. doi: 10.1007/BF00228825.
Basic fibroblast growth factor (bFGF, FGF-2) is a trophic factor for neurons and astrocytes and has recently been demonstrated in the vast majority of dopamine (DA) neurons of the ventral midbrain of the rat. Potential neuroprotective actions of FGF-2 in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model have also been reported. The actions of the FGF-2 have now been further analyzed in a combined morphological and behavioural analysis in the MPTP model of the adult black mouse, using a continuous human recombinant FGF-2 (hrFGF-2) intraventricular (i.v.t.) administration in a heparin-containing (10 IU heparin/ml) mock cerebrospinal fluid (CSF) solution. Tyrosine hydroxylase (TH) immunocytochemistry in combination with computer assisted microdensitometry demonstrated a counteraction of the MPTP-induced disappearance of neostriatal TH-immunoreactive (ir) nerve terminals following the FGF-2 treatment. Unbiased estimates of the total number of nigral TH ir neurons, using stereological methods involving the optical disector (Olympus), showed that the MPTP-induced reduction in the number of nigral TH ir nerve cell bodies counterstained with cresyl violet (CV; by 56%) was partially counteracted by the FGF-2 treatment (by 26%). The behavioral analysis demonstrated an almost full recovery of the MPTP-induced reduction of the locomotor activity after FGF-2 treatment. This action was maintained also 1 week after cessation of treatment. The hrFGF-2 produced an astroglial reaction as determined in the lateral neostriatum and in the substantia nigra (SN) far from the site of the infusion, indicating that the growth factor may have reached these regions by diffusion to activate the astroglia. Immunocytochemistry revealed FGF-2 immunoreactivity (IR) in the nuclei of the astroglia cell population in the dorsomedial striatum and the microdensitometric and morphometric evaluation demonstrated an increase in the number, but not in the intensity, of these profiles on the cannulated side, suggesting the possibility that hrFGF-2 stimulates FGF-2 synthesis in astroglial cells with low endogenous FGF-2 IR. These results indicate that hrFGF-2, directly and/or indirectly via astroglia, upon i.v.t. infusion exerts trophic effects on the nigrostriatal DA system and may increase survival of nigrostriatal DA nerve cells exposed to the MPTP neurotoxin
碱性成纤维细胞生长因子（bFGF，FGF - 2）是一种对神经元和星形胶质细胞具有营养作用的因子，最近已证实在大鼠腹侧中脑的绝大多数多巴胺（DA）神经元中存在该因子。也有报道称FGF - 2在1 - 甲基 - 4 - 苯基 - 1,2,3,6 - 四氢吡啶（MPTP）模型中具有潜在的神经保护作用。现在，在成年黑色小鼠的MPTP模型中，通过形态学和行为学相结合的分析方法，进一步研究了FGF - 2的作用。采用在含肝素（10 IU肝素/毫升）的模拟脑脊液（CSF）溶液中持续脑室内（i.v.t.）注射重组人FGF - 2（hrFGF - 2）。酪氨酸羟化酶（TH）免疫细胞化学结合计算机辅助显微密度测定法显示，FGF - 2治疗后可对抗MPTP诱导的新纹状体TH免疫反应性（ir）神经末梢消失。使用涉及光学分割器（奥林巴斯）的体视学方法对黑质TH ir神经元总数进行无偏估计，结果表明，MPTP诱导的经甲酚紫（CV）复染的黑质TH ir神经细胞体数量减少（减少56%），FGF - 2治疗可部分对抗这种减少（减少26%）。行为学分析表明，FGF - 2治疗后，MPTP诱导的运动活动减少几乎完全恢复。这种作用在治疗停止后1周仍持续存在。hrFGF - 2在远离注射部位的外侧新纹状体和黑质（SN）中引发了星形胶质细胞反应，表明生长因子可能通过扩散到达这些区域以激活星形胶质细胞。免疫细胞化学显示在背内侧纹状体的星形胶质细胞群体的细胞核中有FGF - 2免疫反应性（IR），显微密度测定和形态学评估表明，插管侧这些细胞的数量增加，但强度未增加，这表明hrFGF - 2可能刺激内源性FGF - 2 IR较低的星形胶质细胞中FGF - 2的合成。这些结果表明，hrFGF - 2经脑室内注射后，直接和/或间接通过星形胶质细胞对黑质纹状体DA系统发挥营养作用，并可能增加暴露于MPTP神经毒素的黑质纹状体DA神经细胞的存活率。
