Hossain M A, Fielding K E, Trescher W H, Ho T, Wilson M A, Laterra J
1Department of Neurology, The Johns Hopkins University School of Medicine, USA; 2The Kennedy Krieger Research Institute, Baltimore, MD 21205, USA.
Eur J Neurosci. 1998 Aug;10(8):2490-9.
Fibroblast growth factors (FGFs) are cell mitogens and differentiating factors with neuroprotective properties in the CNS. We have already shown that endothelial cells genetically engineered to secrete human FGF-1 (RBEZ-FGF) survive implantation to neonatal rat brain (Johnston et al. (1996) J. Neurochem. 67, 1643-1652]. In this study, the effects of cell-based FGF-1 gene delivery on quinolinate-induced neurotoxicity in the developing rat brain were examined. Control endothelial cells (RBE4), and RBEZ-FGF cells were implanted into right striatum at post-natal day (PND) 7. On PND 10, quinolinate (150 nmol), an endogenous N-methyl-d-aspartate (NMDA) receptor agonist, or vehicle alone was injected into striatum ipsilateral to cell implantation. Injury was quantified in coronal sections obtained from PND 17 animals by comparing striatal and hippocampal volumes ipsilateral and contralateral to the site of quinolinate injection. Human FGF-1 specific transgene expression in vivo was shown by Northern blot and RT-PCR up to 14 days after cell implantation in control animals, and up to 4 days after quinolinate exposure. Quinolinate reduced the size of ipsilateral striatum by 37% and hippocampus by 38% in animals preimplanted with control endothelial cells. In contrast, quinolinate reduced the size of striatum by only 14% and had no effect on hippocampal size in animals preimplanted with RBEZ-FGF cells. Thus, FGF-1 gene delivery protected the developing striatum and hippocampus from quinolinate-induced volume loss by 62% and 100%, respectively. Intrastriatal quinolinate resulted in a significant decrease in density of NOS+ CA3 hippocampal neurons (-38%) without affecting the density of NOS+ neurons in hippocampal regions CA1, dentate gyrus or striatum. This response of CA3 NOS+ neurons appeared to be only partially reversed by FGF-1 gene delivery. Our results show that intracerebral FGF-1 gene expression within the developing brain can protect striatum and hippocampus from quinolinate-mediated injury.
成纤维细胞生长因子（FGFs）是细胞有丝分裂原和分化因子，在中枢神经系统中具有神经保护特性。我们已经表明，经过基因工程改造以分泌人FGF-1的内皮细胞（RBEZ-FGF）在植入新生大鼠脑内后能够存活（Johnston等人，（1996年）《神经化学杂志》67卷，1643 - 1652页）。在本研究中，检测了基于细胞的FGF-1基因递送对发育中大鼠脑内喹啉酸诱导的神经毒性的影响。在出生后第7天（PND 7），将对照内皮细胞（RBE4）和RBEZ-FGF细胞植入右侧纹状体。在PND 10，将内源性N-甲基-D-天冬氨酸（NMDA）受体激动剂喹啉酸（150 nmol）或单独的溶剂注射到细胞植入同侧的纹状体中。通过比较喹啉酸注射部位同侧和对侧的纹状体和海马体积，对从PND 17动物获得的冠状切片中的损伤进行定量。在对照动物中，通过Northern印迹和RT-PCR显示，在细胞植入后长达14天以及喹啉酸暴露后长达4天，体内存在人FGF-1特异性转基因表达。在预先植入对照内皮细胞的动物中，喹啉酸使同侧纹状体大小减少37%，海马大小减少38%。相比之下，在预先植入RBEZ-FGF细胞的动物中，喹啉酸仅使纹状体大小减少14%，对海马大小没有影响。因此，FGF-1基因递送分别使发育中的纹状体和海马免受喹啉酸诱导的体积损失62%和100%。纹状体内注射喹啉酸导致海马CA3区NOS+神经元密度显著降低（-38%），而不影响海马CA1区、齿状回或纹状体中NOS+神经元的密度。FGF-1基因递送似乎仅部分逆转了CA3区NOS+神经元的这种反应。我们的结果表明，发育中脑内的脑内FGF-1基因表达可以保护纹状体和海马免受喹啉酸介导的损伤。
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