From the patient to the mouse: how clinically-validated anti-seizure medications can perform in a pre-clinical mouse model of MTLE.
Abstract number :
2.33
Submission category :
7. Anti-seizure Medications / 7A. Animal Studies
Year :
2025
Submission ID :
296
Source :
www.aesnet.org
Presentation date :
12/7/2025 12:00:00 AM
Published date :
Authors :
Presenting Author: Maud Muller, PhD – SynapCell
Venceslas Duveau, PhD – SynapCell
Corinne Roucard, PhD – SynapCell
Alexis Evrard, PhD – SynapCell
Rationale: The intrahippocampal kainate mouse model is a model of mesial temporal lobe epilepsy (MTLE), widely used to investigate the physiopathology of this disease. The many common aspects between the animal model and the human pathology include hippocampal sclerosis and non-convulsive focal seizures (hippocampal paroxysmal discharges, HPD) occurring in the affected hippocampus, with occasional convulsive generalized seizures. The model is also used for the preclinical evaluation of candidate anti-seizure medications (ASM). However, several ASM used in the clinic on human patients were never evaluated in this mouse MTLE model. To better bridge the gap between this animal model and the human pathology, we evaluated the effect of a series of validated clinical ASM on the occurrence of HPD in MTLE mice. We selected gabapentine and lacosamide, approved in clinic for focal-onset seizures, ethosuximide, approved for absence epilepsy only, and fenfluramine, approved for the treatment of seizures associated with Dravet and Lennox–Gastaut syndromes. Our work will expand the characterization of the translational validity of the MTLE model for focal-onset seizures.
Methods: Adult male C57BL/6J mice received an intra-hippocampal injection of kainate, as well as a set of electrodes in the dorsal hippocampus for EEG recording of HPD. After 4 weeks of epileptogenesis, animals were validated to confirm a pattern of recurrent HPD. Validated MTLE mice were then used in pharmacological testing with a dose range of an ASM, in a randomized crossover design. Focal seizures were recorded and analysed for 40 min at baseline, and for 130 min after administration. We measured the number and the duration of HPD per 20 min time bins.
Results: The T-type calcium channel blocker ethosuximide (30-300 mg/kg PO) had no significant effect on the number of HPD and induced an extension of their duration. The voltage-dependent calcium channel ligand gabapentin (10-300 mg/kg IP) induced a dose-dependent reduction of HPD, accompanied by a significant reduction of the duration of remaining events. The voltage-gated sodium channel blocker lacosamide induced complete inhibition of HPD at 100 mg/kg IP but the result was accompanied by serious side effects. Lower doses (3-30 mg/kg IP) induced a short-lasting reduction of HPD duration. The 5-HT releasing agent fenfluramine (3-20 mg/kg IP) significantly inhibited HPD, with no effect on their duration.
Conclusions: Our study better characterizes the translational predictivity of the MTLE mouse model for the development of pharmacological tools addressing focal seizures.
Funding: This research was funded by SynapCell.
Anti-seizure Medications