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Angiogenèse: Nouvelle cible thérapeutique pour les épilepsies partielles pharmacorésitantes

Abstract : In Temporal Lobe Epilepsy, hyper excitability is commonly attributed to neuronal loss, gliosis, and synaptic plasticity in the hippocampus. A vascular remodeling has never been investigated in epileptic tissue, although recent data indicate that blood-brain barrier (BBB) permeability is epileptogenic.
In the hippocampus of patients with intractable TLE, we observed vascular changes like BBB leakage, increased vascular density and over expression of Vascular Endothelial Growth Factor (VEGF) and its receptor VEGFR-2.
To understand the mechanisms of this angiogenesis, we used in vivo and in vitro rat models of epilepsy. In vivo, we found neo-vascularization, over expression of VEGF/VEGFR-2 and BBB disruption in a model with neuronal loss and gliosis, whereas in a model without lesion these vascular changes were only transient. In vitro, we showed that seizures, generated in organotypic hippocampal cultures (OHCs), induce angiogenesis and BBB degradation which persist only in presence of lesions.
We investigated in vitro the role of VEGF by neutralizing VEGF or inhibiting different VEGFR-2 signaling pathways in OHCs and confirmed the importance of PKC and src pathways in angiogenesis and BBB degradation. More, we observed a deregulation of angiopoietin ratio in favor of Ang2, which increases VEGF effects.
In humans and animals, angiogenesis and BBB disruption persist in the chronic focus, whereas BBB leakage is known to participate in seizure induction. Therefore, by targeting angiogenic factors, we aim at repairing the BBB and thus reducing epileptogenicity. This study could lead to the development of new therapies for intractable epilepsies.
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https://tel.archives-ouvertes.fr/tel-00421314
Contributor : Mélanie Morin <>
Submitted on : Wednesday, February 3, 2010 - 2:09:01 PM
Last modification on : Tuesday, May 28, 2019 - 2:12:02 PM
Long-term archiving on: : Friday, June 18, 2010 - 6:39:14 PM

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Mélanie Morin. Angiogenèse: Nouvelle cible thérapeutique pour les épilepsies partielles pharmacorésitantes. Neurosciences [q-bio.NC]. Université Montpellier I, 2009. Français. ⟨tel-00421314⟩

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