Angiogenesis is associated with blood-brain barrier permeability in temporal lobe epilepsy. Brain

Centre National de la Recherche Scientifique UMR5203, Université Montpellier 1, Université Montpellier 2, F34094 Montpellier, France.
Brain (Impact Factor: 9.2). 08/2007; 130(Pt 7):1942-56. DOI: 10.1093/brain/awm118
Source: PubMed


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.

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Available from: Valérie Rigau,
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    • "The angiogenic process was confirmed in these patients by detecting high levels of VEGF and overexpression of the receptor tyrosine kinase VEGFR-2 in resected hippocampal tissue (Rigau et al., 2007). Similar results, i.e., increased microvascular density, disruption of BBB, and increased VEGF expression in neurons and astrocytes were found during experimentally induced epileptogenesis in pilocarpine model in rat (Rigau et al., 2007). "
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    ABSTRACT: Epilepsy is one of the most common neurologic disorders affecting a substantial part of the population worldwide. Epileptic seizures represent the situation of increased neuronal activity associated with the enhanced demands for sufficient energy supply. For that purpose, very efficient regulatory mechanisms have to operate to ensure that cerebral blood flow, delivery of oxygen, and nutrients are continuously adapted to the local metabolic needs. The sophisticated regulation has to function in concert at several levels (systemic, tissue, cellular, and subcellular). Particularly, mitochondria play a key role not only in the energy production, but they are also central to many other processes including those leading to neuronal death. Impairment of any of the involved pathways can result in serious functional alterations, neurodegeneration, and potentially in epileptogenesis. The present review will address some of the important issues concerning vascular and metabolic changes in pathophysiology of epilepsy.
    International Review of Neurobiology 08/2014; 114C:209-243. DOI:10.1016/B978-0-12-418693-4.00009-1 · 1.92 Impact Factor
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    • "Serum albumin is observed in neurons, astrocytes and microglial cells after TBI and SE (Seiffert et al., 2004; Ivens et al., 2007; Rigau et al., 2007; Van Vliet et al., 2007a; Ravizza et al., 2008; Ndode-Ekane et al., 2010; Zattoni et al., 2011; Marchi et al., 2011b; Braganza et al., 2012; Frigerio et al., 2012; Michalak et al., 2012, 2013; Bar-Klein et al., 2014). Albumin uptake in neurons might eventually lead to cell death, since it is observed specifically in regions where cell death occurs after SE in rats and humans (Rigau et al., 2007; Van Vliet et al., 2007a). Similarly, IgG uptake is observed in neurons (Michalak et al., 2012). "
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    ABSTRACT: Temporal lobe epilepsy (TLE) is the most common form of focal epilepsies in adults. It is often initiated by an insult or brain injury which triggers a series of alterations which ultimately lead to seizures (epilepsy). In 50-70% of people with TLE the condition cannot be adequately treated by the present antiepileptic drugs. During the last decade the blood-brain barrier (BBB) has received renewed interest as a potential target to treat TLE or its progression. BBB changes have been observed in brain tissue of people with epilepsy as well as in experimental models at the structural, cellular and molecular level that could explain its role in the development and progression of epilepsy (epileptogenesis) as well as the development of drug resistance. Here, we will discuss the role of the BBB in TLE and drug resistance and summarize potential new therapies that may restore normal BBB function in order to put a brake on epileptogenesis and/or to improve drug treatment.
    Neuroscience 07/2014; 277. DOI:10.1016/j.neuroscience.2014.07.030 · 3.36 Impact Factor
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    • "The intrinsic P-gp transport activity in brain capillaries has been suggested to decrease under inflammatory conditions (e.g., upon TNF-a stimulation) and also under pathologic conditions associated with increased expression of vascular endothelial growth factor in brain (Hawkins et al., 2010; Miller, 2010). In the rodent model of epilepsy, protein levels of vascular endothelial growth factor and inflammatory mediators, including TNF-a, in brain are increased after the induction of seizures (Croll et al., 2004; Vezzani and Granata, 2005; Rigau et al., 2007; Vezzani et al., 2011). Therefore, the intrinsic transport activity per P-gp molecule might be decreased in EL mice. "
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    ABSTRACT: The purpose of this study was to demonstrate experimentally that alterations of in vivo transporter function at the blood-brain barrier (BBB) in disease and during pharmacotherapy can be reconstructed from in vitro data based on our established pharmacoproteomic concept of reconstructing in vivo function by integrating intrinsic transport activity per transporter molecule and absolute protein expression level at the BBB. Pentylenetetrazole-kindled (PTZ) and EL mice were used as models of chemically induced and spontaneous epilepsy, respectively. A mouse model of anti-epileptic drug treatment was prepared by consecutive 5-week administration of phenytoin (PHT). Quantitative targeted absolute proteomic analysis of 31 membrane proteins showed that P-glycoprotein (P-gp/mdr1a) protein expression levels were significantly increased in brain capillaries of PTZ (129%), EL (143%), and PHT mice (192%) compared to controls. The brain-to-plasma concentration ratios (Kp brain) of P-gp/mdr1a substrate verapamil were 0.563, 0.394, 0.432, and 0.234 in control, PTZ, EL, and PHT mice, respectively. In vivo P-gp/mdr1a function at the BBB was reconstructed from the measured P-gp/mdr1a protein expression levels and intrinsic transport activity for verapamil per P-gp/mdr1a previously reported by our group. Then, the reconstructed P-gp/mdr1a functional activities were integrated with unbound fractions of verapamil in plasma and brain to reconstruct Kp brain of verapamil. In all mice, reconstructed Kp brain values agreed well with the observed values within a 1.21-fold range. These results demonstrate that altered P-gp functions at the BBB in epilepsy and during pharmacotherapy can be reconstructed from in vitro data by means of our pharmacoproteomic approach.
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