Differential Effects of Antiepileptic Drugs on Focal Seizures in the Intrahippocampal Kainate Mouse Model of Mesial Temporal Lobe Epilepsy

Abstract

The MTLE mouse model displays a differential sensitivity to AEDs with a greater efficacy of drug that facilitates GABAergic transmission. This model provides an efficient tool to identify new treatment for drug-resistant forms of focal epilepsies.

The effects of carbamazepine in the intrahippocampal kainate model of temporal lobe epilepsy depend on seizure definition and mouse strain

“…Therefore, gender differences in the pharmacological response of these mouse strains should be further explored. However, the marked antiseizure effect of 40 mg/kg CBZ observed in the present study in male NMRI mice is clearly in contrast to the previously reported resistance of male mice of other strains to CBZ,5, 35 thus demonstrating a clear strain difference. Furthermore, the data of Leclercq and Kaminski,8 in which the pharmacological response of the 6‐Hz model of difficult‐to‐treat partial seizures was compared in male NMRI, C57BL/6, and CF‐1 mice, showed that male NMRI mice were much more sensitive to ASDs in this model than the two other mouse strains, which is in line with the present findings in epileptic NMRI mice.…”

“…CBZ has been reported to increase interictal spiking in patients and animal models of TLE,47, 48, 49 but this was not systematically evaluated in the present study in the intrahippocampal kainate mouse model of TLE. In a recent study in this model, Duveau et al35 reported that high doses of CBZ (>50 mg/kg) increase the occurrence of interictal spikes. In the latter study, also ictal and interictal power spectra were analyzed, showing an increased power of interictal beta oscillations and an increased amplitude and power of residual HPDs at a dose of CBZ (75 mg/kg i.p.)…”

“…The finding that both HPDs and HVSWs could be suppressed by CBZ in male NMRI mice was unexpected, because previous studies reported that both types of electrographic seizures are resistant to CBZ when administered at doses of 20–50 mg/kg in male and female mice of different strains, including NMRI 5, 6, 10, 35. A similar effect of genetic background on resistance to an ASD (PHT) acting by modulation of sodium channels has recently been reported for the 6‐Hz mouse model of difficult‐to‐treat partial seizures 8.…”

“…Pharmacoresistance in animal models has been operationally defined as persistent seizure activity that does not respond to monotherapy at tolerable doses with at least two current ASDs 50. Thus, antiseizure efficacy of ASDs such as CBZ and of other ASDs at high neurotoxic doses as reported by Duveau et al35 in the intrahippocampal kainate mouse model are difficult to interpret. On the basis of previous pharmacokinetic analyses in mice,51 plasma concentrations achieved at time of maximum antiseizure effect of CBZ (15 min) at the doses used in the present study would be 7.3 μg/ml (20 mg/kg) and 14.5 μg/ml (40 mg/kg), which is closely related to the “therapeutic plasma concentration range” (4–12 μg/ml) in patients with epilepsy 52.…”

High-Throughput LC–MS/MS Proteomic Analysis of a Mouse Model of Mesiotemporal Lobe Epilepsy Predicts Microglial Activation Underlying Disease Development

“…It reproduces most of the behavioral, electrophysiological, histological and pharmacological features observed in human patients suffering of MTLE, as depicted by clinical epileptologists 47,90,91 . A large number of publications have used this model including recent investigations on the most commonly used antiepileptic drugs [13][14][15][16]47 .…”