Exploring the P-glycoprotein-mediated efflux transport at the blood-brain barrier as a biomarker of drug-resistance in focal epilepsy – EPIFLUX

Epilepsy is one of the most common serious neurological disorders, affecting approximately 65 million people worldwide. Seizures can be controlled by antiepileptic drugs (AEDs) in most cases. However, ~30% of patients have drug-resistant epilepsy (DRE) and experience debilitating refractory seizures. This has prompted the search for biomarkers to detect, distinguish, predict or follow DRE and to address the multifactorial nature of epilepsy and its heterogeneity. Surgery is often proposed as the final remedy to stop seizures and improve quality of life. Efforts are being made to optimize invasive monitoring or neuroimaging methods to precisely delineate epileptogenic areas which is a prerequisite for surgical resection. Focal seizures may be unifocal, when only one area of the brain is involved at onset. Multifocal epilepsy involves several different areas of the brain which limits the applicability of surgery.

Suboptimal brain exposure to AEDs and limited access to their CNS targets through the blood-brain barrier (BBB) is assumed to contribute to DRE. Many AEDs are substrates of P-glycoprotein (P-gp), a major efflux drug transporter at the BBB, which can control their brain exposure. Upregulation of P-gp has been consistently observed in resected or post-mortem epileptic brain tissue. Increased P-gp staining contrasted with the healthy brain tissue and was much higher in patients with DRE compared with drug-sensitive patients or healthy controls. This raised the relevance of focal P-gp upregulation as a biomarker of DRE and prompted the need for a clinically feasible method to estimate P-gp function at the BBB in patients.
Transporter function at the human BBB can be non-invasively studied using Positron Emission Tomography (PET) imaging in combination with radiolabeled substrate radiotracers. We have validated metoclopramide radiolabeled with carbon-11 (11C-metoclopramide) as a PET probe to safely and specifically study P-gp function at the BBB in animals and healthy humans. 11C-metoclopramide PET imaging has been designed and optimized to non-invasively detect P-gp upregulation in the living brain.

The objective of the project is to evaluate 11C-metoclopramide PET imaging for the first time in patients with epilepsy and address the relevance of P-gp function as a biomarker of DRE. To this end, the P-gp mediated efflux of 11C-metoclopramide will be assessed
- in the brain of patients with nonlesional DRE, assuming that the epileptic focus can be spatially localized against healthy tissues based on regional P-gp overexpression
- in the brain and lesional (localized, temporal lobe) focus of patients with DRE in comparison with drug-sensitive patients and healthy controls
- In the brain of patients with multifocal DRE, thus investigating the hypothesis of heterogeneity in drug-resistance between foci

The EPIFLUX project is led by young scientists and carried out by two multidisciplinary research teams (SHFJ in Orsay, France and the Medical University of Vienna, Austria). The project is designed to validate a much-needed imaging method to study P-gp function at the BBB of patients with DRE. The project will foster the main clinical application of 11C-metoclopramide PET imaging which was initially developed by CEA-SHFJ as a probe to investigate P-gp function as a variability factor for neuropharmacology. The project will benefit from the ample expertise of the Vienna team in conducting clinical PET experiments to study P-gp in patients with epilepsy, which led to major publications in the field. We expect this pioneer work to be extended and brought to clinical and diagnostic applications through this collaborative project using a tailored and clinically feasible PET protocol. Our ambition is to pave the way for the use of 11C-metoclopramide PET as a diagnostic biomarker to localize and characterize epileptogenic foci associated with DRE and provide functional information for a molecularly-targeted management of DRE.