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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    • "Proliferation of endothelial cells, increased vessel density, increased expression of angiogenic factors such as vascular endothelial growth factor (VEGF) in neurons as well as VEGF tyrosine kinase receptors on blood vessels occur after SE and are most prominent within the CA3 region of the hippocampus (Morin-Brureau et al., 2012), as also demonstrated in our study with the most increased endothelial cells numbers in the CA3 region. The new vessels tend to be leaky resulting in blood-brain barrier impairment as demonstrated by loss of tight junctions that leads to extravasation of ions and serum proteins into the extracellular environment, triggers inflammation, leads to neuronal dysfunction and ultimately promotes seizures (Morin-Brureau et al., 2012;Hallene et al., 2006;Rigau et al., 2007). Presently, medical management of seizures involves only a symptomatic approach that increases the brain's threshold for seizure generation but does not cure or alter the course of this mor-bid disease. "
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    • "Both antibody-mediated mechanisms and T-cell cytotoxicity can be involved in epilepsy and other seizure-related disorders. Investigations of the brains of patients with long-standing epilepsies have shown changes indicative of BBB damage with evidence of albumin and IgG extravasation in brain parenchyma (Rigau et al. 2007;van Vliet et al. 2007;Ravizza et al. 2008), although it is unclear how the BBB becomes compromised initially. More recently, a direct role has also been suggested for autoantibodies in seizure-related diseases, such as RE, forms of viral encephalitis, and encephalitides, which are defined by the presence of specific neural antibodies in serum and/or CSF (Table 1). "
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    • "The latter is significant considering the contribution of pericytes to microvascular integrity (Dore-Duffy, 2008;Daneman et al., 2010;Winkler et al., 2011). Increased cerebrovascular permeability and dysregulated angiogenesis provoke or sustain seizures in experimental and human epilepsy (Seiffert et al., 2004;Marchi et al., 2007;Rigau et al., 2007;van Vliet et al., 2014). In the present study we refer to perivascular PDGFRb + cells as pericytes (Armulik et al., 2005;DoreDuffy, 2008;Winkler et al., 2011), while not specifying the exact nature of parenchymal PDGFRb immunoreactivity (Birbrair et al., 2013Birbrair et al., , 2014aBirbrair et al., ,b, 2015FernandezKlett et al., 2013;Matsumoto et al., 2014). "
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