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

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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