Brain Advance Access originally published online on May 28, 2007
Brain 2007 130(7):1942-1956; doi:10.1093/brain/awm118
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Angiogenesis is associated with blood–brain barrier permeability in temporal lobe epilepsy
1Centre National de la Recherche Scientifique UMR5203, Université Montpellier 1, Université Montpellier 2, F34094 Montpellier, 2Institut de la Santé et de la Recherche Medicale U661, F34094 Montpellier, 3CHU, Laboratoire d’ Anatomie et Cytologie Pathologiques, F34295 Montpellier and 4CHU, Unité d’ Epileptologie, F34295 Montpellier
Correspondence to: Mireille Lerner-Natoli, PhD, Institut de Génomique Fonctionnelle, 141 rue de la Cardonille, 34094 Montpellier Cedex 5, France E-mail: mireille.lerner-natoli{at}igf.cnrs.fr
Previous studies from our group, focusing on neuro-glial remodelling in human temporal lobe epilepsy (TLE), have shown the presence of immature vascular cells in various areas of the hippocampus. Here, we investigated angiogenic processes in hippocampi surgically removed from adult patients suffering from chronic intractable TLE, with various aetiologies. We compared hippocampi from TLE patients to hippocampi obtained after surgery or autopsy from non-epileptic patients (NE). We quantified the vascular density, checked for the expression of angiogenic factors and their receptors and looked for any blood–brain barrier (BBB) leakage. We used a relevant model of rat limbic epilepsy, induced by lithium-pilocarpine treatment, to understand the sequence of events.
In humans, the vessel density was significantly higher in TLE than in NE patients. This was neither dependent on the aetiology nor on the degree of neuronal loss, but was positively correlated with seizure frequency. In the whole hippocampus, we observed many complex, tortuous microvessels. In the dentate gyrus, when the granular layer was dispersed, long microvessels appeared radially orientated. Vascular endothelial factor (VEGF) and tyrosine kinase receptors were detected in different types of cells. An impairment of the BBB was demonstrated by the loss of tight junctions and by Immunoglobulines G (IgG) leakage and accumulation in neurons. In the rat model of TLE, VEGF over-expression and BBB impairment occurred early after status epilepticus, followed by a progressive increase in vascularization. In humans and rodents, angiogenic processes and BBB disruption were still obvious in the chronic focus, probably activated by recurrent seizures. We suggest that the persistent leakage of serum IgG in the interstitial space and their uptake by neurons may participate in hypoperfusion and in neuronal dysfunction occurring in TLE.
Key Words: temporal lobe epilepsy; angiogenesis; vascular endothelial growth factor; blood-brain barrier disruption; IgG leakage
Abbreviations: AVM, arterio-venous malformation; CRYPTO, cryptogenetic; DG, dentate gyrus; DGL, dentate granular layer; DNET, dysembryoplastic neuroepithelial tumour; DYSP, focal dysplasia; Ext-TLE, external temporal lobe epilepsy; FH, fissura hippocampi; GG, ganglioglioma; HA, hippocampal atrophy; HS, hippocampal sclerosis; ISCH, ischemia; SE, status epilepticus; SGL, subgranular layer; SVZ, sub-ventricular zone; TLE, temporal lobe epilepsy; VEGF, vascular endothelial growth factor; ZO-1, zonula occludens-1.
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Received December 29, 2006. Revised April 12, 2007. Accepted April 30, 2007.
*These authors contributed equally to this work.