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。研究人员提出了脑缺血后bFGFmRNA和即刻早期基因(IEGs)的表达，以及bFGF对改善脑梗塞体积的神经保护作用等研究项目。得到了以下结果。(1)短暂性局灶性脑缺血后碱性成纤维细胞生长因子基因的表达：碱性成纤维细胞生长因子基因在再灌流后6~48h在梗死灶周围皮质和尾壳核均有明显表达，5d后消失。在双侧海马区、扣带回皮质等偏远区域也可观察到碱性成纤维细胞生长因子表达。碱性成纤维细胞生长因子的表达主要集中在神经元和神经胶质细胞。以往的报道表明，在梗死灶周围区域，bFGF受体mRNA表达上调。损伤组织释放的内源性碱性成纤维细胞生长因子可通过自身旁分泌方式影响愈合反应。由于IEGs先于bFGF mRNA的表达，IEGs可能调节bFGF的转录(Iwata A等人，《神经创伤杂志》1997)。(2)静脉注射碱性成纤维细胞生长因子对脑梗塞面积的影响：制作大鼠永久性局灶性脑缺血模型。缺血30min后，用渗透压微泵静脉注射重组人碱性成纤维细胞生长因子，连续3d。碱性成纤维细胞生长因子治疗组大鼠的脑梗塞体积明显小于生理盐水对照组。剂量依赖关系在0.4至2mug/kg/hr之间。当剂量为10µg/kg/h时，脑梗塞体积增大，可能是由于低血压所致。脑梗塞面积缩小以皮质明显，尾壳核不明显。我们的研究证实，长期低剂量静脉注射碱性成纤维细胞生长因子对局灶性脑缺血有潜在的神经保护作用，且没有全身副作用。(3)正在进行的项目：行为和生理影响的调查正在进行中。

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.