Application of FGF to the restoration of ischemic brain damage

本研究旨在探讨碱性成纤维细胞生长因子（bFGF）在缺血性脑损伤修复中的应用。研究者提出了脑缺血后bFGF mRNA和即刻早期基因（immediate early genes，IEGs）表达的研究项目，以及bFGF改善梗死体积的神经保护作用。获得了以下结果。（1）短暂局灶性脑缺血后bFGF基因的表达：再灌注后6-48小时，bFGF mRNA在梗死周围皮质和尾壳核有明显表达，5天后表达消失。bFGF在双侧海马、扣带回等远隔区也有表达。bFGF mRNA信号主要集中在神经元和胶质细胞。以往的研究表明，bFGF受体mRNA在梗死灶周围表达上调。损伤组织释放的内源性bFGF可通过自旁分泌方式影响愈合反应。因为IEG先于bFGF mRNA表达，所以IEG可能调节bFGF转录（岩田A等，神经创伤杂志1997）.（2）静脉注射bFGF对脑梗死范围的影响：制作大鼠永久性局灶性脑缺血模型。在缺血开始后30分钟，使用渗透微型泵静脉内给予人重组bFGF 3天。bFGF处理组大鼠的脑体积明显小于生理盐水处理组。在0.4至2 μ g/kg/h范围内存在剂量依赖性。在10 μ g/kg/h剂量下，颅内压体积增加，可能是低血压的结果。脑梗死面积缩小在皮质较尾壳核明显。我们的研究证实，长期和低剂量的bFGF静脉给药对局部缺血有潜在的神经保护作用，而无全身副作用。（3）进行中的项目：行为和生理影响的研究正在进行中。

The present study was designed to investigate the application of basic fibroblast growth factor (bFGF) to restoration of ischemic cerebral damage. The investigators proposed research projects such as expression of bFGF mRNA and immediate early genes (IEGs) after the cerebral ischemia, and the neuroprotective effects of bFGF to ameliorate infarction volume. The following results were obtained. (1)EXPRESSION OF bFGF GENE AFTER TRANSIENT FOCAL ISCHEMIA : bFGF mRNA was markedly expressed in the peri-infarct cortex and caudoputamen during 6-48 hr after the reperfusion, and disappeared by 5 days. The expression of bFGF was also observed in the remote areas such as bilateral hippocampus and cingulate cortex. Signals of bFGF mRNA focused on neurons and glial cells. Previous reports showed that bFGF receptor mRNA was upregulated in the peri-infarct areas. Intrinsic bFGF released from the damaged tissue could influence the healing response through the auto-paracrine manner. Because IEGs preceded the bFGF mRNA expression, IEGs might regulate the bFGF transcription (Iwata A et al.J Neurotrauma 1997). (2)THE EFFECTS OF INTRAVENOUS bFGF ADMINISTRATION ON THE INFARCT SIZE : Permanent focal ischemia was made in rats. Thirty min after the initiation of ischemia, human recombinant bFGF was given intravenously for 3 days using osmotic minipumps. Infarct volumes in the rats treated with bFGF were significantly smaller than in the saline treated controls. Dose-dependency was present within 0.4 to 2 mug/kg/hr. Infarct volume increased at the dose of 10 mug/kg/h, probably as a result of hypotension. The reduction of infarction size was obvious in cortex rather than in caudate-putamen. Our study confirmed that long-term and low-dose intravenous administration of bFGF was potentially neuroprotective against focal ischemia without systemic side effects. (3)ONGOING PROJECT : The investigation of behavioral and physiological effects are in progress.