CEREBROVASCULAR DYNAMICS IN EPILEPSY: ENDOTHELIAL-PERICYTE INTERFACE – Epicyte

Epilepsy is a severe neurological disorder characterized by spontaneous recurrent seizure activity. This disease affects up to 1% of the population worldwide, representing solely in the EU a clinical annual cost of 15.5 billion euros. About 30% of the epileptic patients do not respond to available antiepileptic drugs (AED) and resective brain surgery represents the last clinical resort. Accumulating evidence has indicated cerebrovascular damage as a key pathophysiological player in experimental and clinical epilepsy. A cerebrovascular oriented approach to epilepsy has recently delivered numerous lines of evidence on how vascular dysfunction and permeability of the blood brain barrier (BBB) negatively impact neuronal activity. The BBB is a tightly controlled assembly of endothelial cells, astrocytes and pericytes sealed by a basal lamina and directly contributing to physiological neuronal activity. In particular, the pathophysiological role of pericytes and their interplay with endothelial cells are attracting increasing attention. Pericytes are mural cells forming a tight sleeve around the cerebral microvessels, covering approximately 60-70% of the abluminal vascular surface and participating in the control of cerebrovascular stability, permeability, growth and hemodynamics. Our recently published results and preliminary data have revealed pericyte-endothelial pathological changes after status epilepticus in animal models and in drug-resistant epileptic patients.

Building from published data and new preliminary results, Partners 1 and 2 have designed a translational workplan to define the dynamics of pericyte cerebrovascular changes in the epileptic brain, improving our understanding of the pathophysiology and the clinical diagnosis of epilepsies. This workplan includes multi-modal cerebrovascular imaging during epileptogenesis in vivo using experimental models of chronic epilepsy and in epileptic patients prior to surgery. We will exploit pericytes as an entry point to decipher the impact of cerebrovascular dysfunction in the epileptic brain on specific vascular MRI read-out in vivo. We will target pericyte-endothelial cell signalling to prevent or diminish cerebrovascular damage and seizure activity.

Our proposal has clinical impact with the potential to deliver: i) pericyte damage as a novel mechanism of disease; ii) pericyte signalling as a novel pharmacological target; iii) specific vascular MRI read-outs matching cellular changes and of pre-operative diagnostic value. Pericyte pathology occurring over-time could represent the "missing link" between cellular and functional cerebrovascular changes. Pathological modifications occurring in the microvasculature in the seizures onset zone could be challenged as new histological and MRI biomarkers of epileptogenic maps.