BACKGROUND: Fibroblast growth factors (FGFs) play a role in neuronal survival after brain ischemia when administered intrace-rebrally. However, the clinical problems that chronic intracerebral infusion of FGFs involves may restrict its use. The purpose of this study was to analyze if FGFs administered intravenously might afford neuroprotection against transient brain ischemia in the light of new published data that suggest that these polypeptides cross the blood brain-barrier (BBB). METHODS: The efficacy of acidic fibroblast growth factor (aFGF) treatment was analyzed in a gerbil model of 5 min forebrain ischemia followed by 7 days of reperfusion. Native and nonmitogenic aFGF was injected in gerbils as a bolus through a jugular vein at the onset of reperfusion. Control animals received in the same manner vehicle solution alone. Seven days later, neuroprotection was evaluated histologically. Penetration of the FGF across the BBB was assessed by autoradiographic studies in rats. For that purpose, we injected through the jugular vein 0.1 microgram of uniformly labeled native 14C-basic fibroblast growth factor (bFGF), 0.1 microgram of heat-denatured 14C-bFGF, or a coinjection of 14C-bFGF with a 900-fold excess of unlabeled bFGF. Two hours later, animals were killed for morphological studies. RESULTS: We report that a venous injection of either native or nonmitogenic form of aFGF after 5 min forebrain ischemia in the gerbil significantly reduced the occurrence of delayed neuronal death (DND) in the CA1 sector of the hippocampus. We also confirmed that blood-borne 14C-bFGF accumulates in CA1 pyramidal neurons.
BACKGROUND: Fibroblast growth factors (FGFs) play a role in neuronal survival after brain ischemia when administered intrace-rebrally. However, the clinical problems that chronic intracerebral infusion of FGFs involves may restrict its use. The purpose of this study was to analyze if FGFs administered intravenously might afford neuroprotection against transient brain ischemia in the light of new published data that suggest that these polypeptides cross the blood brain-barrier (BBB). METHODS: The efficacy of acidic fibroblast growth factor (aFGF) treatment was analyzed in a gerbil model of 5 min forebrain ischemia followed by 7 days of reperfusion. Native and nonmitogenic aFGF was injected in gerbils as a bolus through a jugular vein at the onset of reperfusion. Control animals received in the same manner vehicle solution alone. Seven days later, neuroprotection was evaluated histologically. Penetration of the FGF across the BBB was assessed by autoradiographic studies in rats. For that purpose, we injected through the jugular vein 0.1 microgram of uniformly labeled native 14C-basic fibroblast growth factor (bFGF), 0.1 microgram of heat-denatured 14C-bFGF, or a coinjection of 14C-bFGF with a 900-fold excess of unlabeled bFGF. Two hours later, animals were killed for morphological studies. RESULTS: We report that a venous injection of either native or nonmitogenic form of aFGF after 5 min forebrain ischemia in the gerbil significantly reduced the occurrence of delayed neuronal death (DND) in the CA1 sector of the hippocampus. We also confirmed that blood-borne 14C-bFGF accumulates in CA1 pyramidal neurons.