Targeting of Glutamate Ionotropic Receptor Kainate for the Treatment of Focal Epilepsy
Stephane Baudouin1, Christophe Mulle2, Richard Porter1, Alfonso Represa3, Valerie Crepel3
1uniQure AG, Basel, Switzerland, 2Univ. Bordeaux, CNRS, Interdisciplinary Institute for Neuroscience, IINS, UMR 5297, F-33000 Bordeaux, France, 3Aix-Marseille Univ. INSERM, INMED, Marseille, France
Objective:
The objective of this study was to determine if inhibiting Glutamate Ionotropic Receptor Kainate (KAR) activity using small molecules can be a therapeutic strategy for focal cortical dysplasia (FCD).
Background:
Focal Cortical Dysplasia (FCD) is a cortical developmental malformation responsible for drug-resistant epilepsies in both children and adults representing around 20% of individuals who undergo epilepsy surgery. We recently demonstrated that either antagonising with a small molecule or knocking down the expression of kainate receptors (KARs) leads to a reduction of epileptic discharges and epileptiform activities in slices prepared from patients with refractory temporal lobe epilepsy (TLE). KARs have also been associated with other forms of focal and generalized epilepsy in animal models and humans. In this study, we sought to expand upon these findings to investigate whether blocking KARs could play a role in controlling neuronal hyperexcitability in neocortical epilepsies, mainly FCD.
Design/Methods:
Cortical organotypic slices from TLE and FCD patients and from a rat model of FCD were treated with UBP130, a non-specific KAR inhibitor. The efficacy of UBP130 in cortical organotypic slices was recorded using electrophysiological local field potential.
Results:
Application of 5 µM UBP310 (in conditions promoting epileptic discharges: 50 µM 4-AP and 5 µM gabazine) reduced the frequency of recurrent epileptiform discharges in cortical organotypic slices from patients with FCD and patients with TLE. Application of the same dose of 5 µM UBP310 significantly reduced the frequency of epileptiform discharges in cortical organotypic slices from a rat model of FCD. Similar results were found with cortical organotypic slices from patients with TLE.
Conclusions:
Using similar experimental approaches on cortical organotypic slices from FCD and TLE patients showed that inhibition of KARs led to a reduction of neuronal network hyperexcitability.