INTRAVENOUS FIBROBLAST GROWTH-FACTOR PENETRATES THE BLOOD-BRAIN-BARRIER AND PROTECTS HIPPOCAMPAL-NEURONS AGAINST ISCHEMIA-REPERFUSION INJURY

BACKGROUND Fibroblast growth factors (FGFs) play a role in neuronal su rvival after brain ischemia when administered intracerebrally. However , the clinical problems that chronic intracerebral infusion of FGFs in volves may restrict its use. The purpose of this study was to analyze if FGFs administered intravenously might afford neuroprotection agains t transient brain ischemia in the light of new published data that sug gest that these polypeptides cross the blood brain-barrier (BBB). METH ODS The efficacy of acidic fibroblast growth factor (aFGF) treatment w as analyzed in a gerbil model of 5 min forebrain ischemia followed by 7 days of reperfusion. Native and nonmitogenic aFGF was injected in ge rbils as a bolus through a jugular vein at the onset of reperfusion. C ontrol animals received in the same manner vehicle solution alone. Sev en days later, neuroprotection was evaluated histologically. Penetrati on of the FGF across the BBB was assessed by autoradiographic studies in rats. For that purpose, we injected through the jugular vein 0.1 mu g of uniformly labeled native C-14-basic fibroblast growth factor (bF GF), 0.1 mu g of heat-denatured C-14-bFGF, or a coinjection of C-14-bF GF 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 f orebrain ischemia in the gerbil significantly reduced the occurrence o f delayed neuronal death (DND) in the CA1 sector of the hippocampus. W e also confirmed that blood-borne C-14-bFGF accumulates in CA1 pyramid al neurons. (C) 1998 by Elsevier Science Inc.