Authors :
Alexis Evrard, PhD – SynapCell
Presenting Author: Hugo Monchal, MSc – SynapCell
Corinne Roucard, PhD – SynapCell
Venceslas Duveau, PhD – SynapCell
Rationale:
Genetic absence epilepsy rat from Strasbourg (GAERS) is an inbred strain of Wistar rats selected for their spontaneous spike-and-wave discharges (SWD). GAERS have become a reference preclinical model of absence seizures. Their characteristics are translational, including behavioural, electrophysiological and pharmacological features similar to the human pathology.
Cortical EEG recordings in GAERS are characterized by SWD lasting 17-25 sec, with a recurrence of 45-70 seizures per hour. The preclinical measurement of SWD in GAERS can predict the effect of a test compound in patients, the pharmacological sensitivity being particularly similar in the two situations. Indeed, SWD in GAERS are inhibited by the anti-seizure medications (ASM) used to treat absence seizures, such as ethosuximide, valproate and lamotrigine. But SWD in GAERS are also aggravated by ASM or other drugs known for worsening absence in patients, e.g. carbamazepine or vigabatrin.
Some recent compounds with antiseizure properties and specific mechanisms of action have never been evaluated in the GAERS. We evaluated retigabine, a voltage-gated potassium channel opener, and fenfluramine, a 5-HT releasing agent. We also enrolled lamotrigine, a voltage-gated sodium channel blocker, in the study for comparison.Methods:
Adult male GAERS were implanted under anaesthesia with cortical electrodes for the EEG recording of SWD. After recovery and validation of the EEG signals, animals were enrolled in a compound testing. A randomized crossover design was used to evaluate dose ranges of test compounds, and a vehicle control was included. The EEG signals were recorded at baseline for at least 40 min before administration, and for at least 130 min after administration. The number and the duration of SWD were quantified over the duration of EEG recordings.
Results:
Lamotrigine (10-40 mg/kg IP) induced a dose-dependent reduction of the number of SWD, with a near complete inhibition at the highest dose. The duration of remaining SWD remained unchanged after treatment at all doses. Retigabine (4-8 mg/kg PO) produced a significant aggravation of SWD. The number of SWD increased significantly for the 2 hours after administration at 8 mg/kg. The duration of SWD remained however unchanged. Fenfluramine (3-30 mg/kg IP) induced a dose-dependent reduction of the number of SWD, reaching ~90% from baseline at the maximum dose. In addition, fenfluramine induced a partial reduction of the duration of the remaining SWD.Conclusions:
Evaluation of new mechanisms of action in the GAERS may provide fresh hypothesis for the development of new compounds addressing absence seizures. Our study indicates that targeting potassium channels may be at risk of aggravating SWD, whereas targeting the 5-HT system may produce an interesting effect on absence seizures.Funding: This project was funded by SynapCell.