Elsevier

Surgical Neurology

Volume 49, Issue 1, January 1998, Pages 77-84
Surgical Neurology

Original Articles
Intravenous Fibroblast Growth Factor Penetrates the Blood-Brain Barrier and Protects Hippocampal Neurons Against Ischemia-Reperfusion Injury

Parts of the present results have been described in proceedings presented at the IVth IWCVS at Chicago 1995.
https://doi.org/10.1016/S0090-3019(97)00193-6Get rights and content

Abstract

Background

Fibroblast growth factors (FGFs) play a role in neuronal survival after brain ischemia when administered intracerebrally. 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 μg of uniformly labeled native 14C-basic fibroblast growth factor (bFGF), 0.1 μg 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.

Section snippets

Material and Methods

Animal care procedures were conducted in accordance with the guidelines set by the European Community council directives 86/6091 EEC.

Analysis of Rat Hippocampal Autoradiograms

Our specific experimental approach to the study of the efficiency of the intravenous administration of FGFs to protect brain tissues from the effects of transient ischemia was undertaken on the assumption that these proteins are able to cross the BBB after systemic administration. Therefore, we studied previously if FGFs effectively accumulate in the hippocampus, a region where the effects of transient ischemia are depicted most strikingly. Histological autoradiograms effectively showed

Discussion

This article presents data showing that systemic administration of FGFs protects hippocampal neurons against ischemia/reperfusion injury. Our results also show that an engineered aFGF lacking mitogenic activity affords efficient protection, too. Recognition of FGFs by their cell membrane receptors evokes a cascade of early and late intracellular events 1, 30, 31. It seems that early events are not enough to trigger mitogenesis [30]. Nevertheless, they seem sufficient for sustaining some other

Acknowledgements

This work was supported by CICYT and Fundación Gregorio Marañon- and Fundación Futuro-Boehringer Ingelheim España S.A. agreements. Human recombinant 14C-bFGF used in these studies was provided by Dr. Y. Courtois (Unité de Recherches Gérontologiques, INSERM, Paris), to whom we express our gratitude. We are also grateful to Dr.. I. Saenz de Tejada for criticisms and C. Bourdier for editorial assistance.

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