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Effects of basic fibroblast growth factor on neuron death and learning disability

碱性成纤维细胞生长因子对神经元死亡和学习障碍的影响

基本信息

批准号：
08680821
负责人：
SAKANAKA Masahiro
金额：
$ 1.79万
依托单位：
Ehime University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
1996
资助国家：
日本
起止时间：
1996 至 1998
项目状态：
已结题

项目摘要

Platelet factor 4(PF4), which has a potent affinity for hparin, has shown to inhibit the binding of basic fibroblast growth factor (bFGF) to the cell surface receptor and to counteract the biological activities of bFGF in certain peripheral tissues. In the present in vitro [^<125>I] bFGF binding experiments, the affinity of [^<125>I] bFGF with the receptor was shown to be higher in the ischemic hippocampus than in the normal hippocampus and PF4 consistently inhibited the binding of indicated bFGF to cell membranes of the gerbil hippocampus. To investigate the in vivo function of endogenous bFGF and/or bFGF receptor possibly activated in the ischemic gerbil brain, we infused PF4 continuously into the left lateral ventricle through an osmotic minipump. When PF4 infusion was started within three days after a 3-min ischemic insult, it significantly enhanced ischemia-induced learning disability and ischemic neuronal loss in the CA1 region of the hippocampus, as demonstrated by the results o … More f a step-down passive avoidance task and by subsequent histological examinations. Infusion of PF4 into the cerebral ventricle of intact gerbils did not affect leaning ability or CA1 neuron number. bFGF-neutralizing antibody, when infused continuously in the cerebral ventricle, also exhibited a neurotoxic effect in ischemic but not intact gerbils. bFGF co-infused with heparin, but not bFGF alone, rescued a significant number of ischemic neurons which were destined to degenerate without the infusion of heparinized bFGF, and it prevented ischemia-induced learning disability. bFGF infusion prior to PF4 treatment abolished almost completely the neurotoxic effect of PF4 on the ischemic hippocampal CA1 region. These findings suggest that (1) PF4 as a putative bFGF receptor antagonist exerts a neurotoxic effect on the ischemic hippocampus and so does bFGF-neutralizing antibody ; (2) heparin is indispensible for bFGF to retain neurotrophic activity ; (3) bFGF infused before PF4 treatment occupies the binding sites of bFGF on the cell surfaces of ischemic neurons ; and (4) the later infusion of PF4, even though it blockes, partially, the subsequent binding of bFGF to the receptor, can no longer suppress the bFGF-mediated intracellular signal transduction in favor of neuronal survival. Thus, the present study indicates a pivotal role of endogenous bFGF in the survival and functional recovery of ischemic neurons. In the present study, the neuroprotective effect of heparinized bFGF was also compared with those of other growth factors, cytokines and drugs such as interleukin 6, platelet-derived growth factor, beta-estradiol, TEI-7165, ginsenoside Rb1, epidermal growth factor, erythropoietin and interleukin 3. Less

血小板因子 4 (PF4) 对肝素具有很强的亲和力，可抑制碱性成纤维细胞生长因子 (bFGF) 与细胞表面受体的结合，并抵消 bFGF 在某些外周组织中的生物活性。在目前的体外[^ 125 I]bFGF结合实验中，显示[^ 125 I]bFGF与受体的亲和力在缺血海马中比在正常海马中更高，并且PF4始终抑制所示bFGF与沙鼠海马细胞膜的结合。为了研究缺血沙鼠脑中可能激活的内源性bFGF和/或bFGF受体的体内功能，我们通过渗透微型泵将PF4持续注入左侧脑室。当 3 分钟缺血性损伤后三天内开始 PF4 输注时，它显着增强了缺血引起的学习障碍和海马 CA1 区域缺血性神经元损失，这一点通过降级被动回避任务的结果和随后的组织学检查得到证明。将 PF4 注入完整沙鼠的脑室不会影响倾斜能力或 CA1 神经元数量。当bFGF中和抗体持续注入脑室时，对缺血但完整的沙鼠也表现出神经毒性作用。 bFGF 与肝素共同输注，而不是单独输注 bFGF，可以挽救大量缺血性神经元，这些神经元在不输注肝素化 bFGF 的情况下注定会退化，并且可以预防缺血引起的学习障碍。在 PF4 治疗之前输注 bFGF 几乎完全消除了 PF4 对缺血海马 CA1 区域的神经毒性作用。这些发现表明：(1) PF4 作为一种假定的 bFGF 受体拮抗剂，对缺血海马产生神经毒性作用，bFGF 中和抗体也有这种作用； (2)肝素对于bFGF保持神经营养活性是不可或缺的； (3)PF4治疗前输注的bFGF占据了缺血神经元细胞表面bFGF的结合位点； (4)稍后输注PF4，即使它部分阻断bFGF随后与受体的结合，也不能再抑制bFGF介导的有利于神经元存活的细胞内信号转导。因此，本研究表明内源性 bFGF 在缺血神经元的存活和功能恢复中发挥着关键作用。本研究还比较了肝素化bFGF的神经保护作用与其他生长因子、细胞因子和药物如白细胞介素6、血小板源性生长因子、β-雌二醇、TEI-7165、人参皂苷Rb1、表皮生长因子、促红细胞生成素和白细胞介素3的神经保护作用。