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. 2018 Nov;59(11):2035-2048.
doi: 10.1111/epi.14563. Epub 2018 Oct 17.

Recurrent epileptiform discharges in the medial entorhinal cortex of kainate-treated rats are differentially sensitive to antiseizure drugs

Peter J West  1   2   3 , Gerald W Saunders  2 , Peggy Billingsley  2 , Misty D Smith  1   2   4 , H Steve White  5 , Cameron S Metcalf  1   2 , Karen S Wilcox  1   2   3
Affiliations

Recurrent epileptiform discharges in the medial entorhinal cortex of kainate-treated rats are differentially sensitive to antiseizure drugs

Peter J West et al. Epilepsia. 2018 Nov.

Abstract

Objective: Approximately 30% of patients with epilepsy are refractory to existing antiseizure drugs (ASDs). Given that the properties of the central nervous systems of these patients are likely to be altered due to their epilepsy, tissues from rodents that have undergone epileptogenesis might provide a therapeutically relevant disease substrate for identifying compounds capable of attenuating pharmacoresistant seizures. To facilitate the development of such a model, this study describes the effects of classical glutamate receptor antagonists and 20 ASDs on recurrent epileptiform discharges (REDs) in brain slices derived from the kainate-induced status epilepticus model of temporal lobe epilepsy (KA-rats).

Methods: Horizontal brain slices containing the medial entorhinal cortex (mEC) were prepared from KA-rats, and REDs were recorded from the superficial layers. 6-cyano-7-nitroquinoxaline-2,3-dione, (2R)-amino-5-phosphonovaleric acid, tetrodotoxin, or ASDs were bath applied for 20 minutes. Concentration-dependent effects and half maximal effective concentration values were determined for RED duration, frequency, and amplitude.

Results: ASDs targeting sodium and potassium channels (carbamazepine, eslicarbazepine, ezogabine, lamotrigine, lacosamide, phenytoin, and rufinamide) attenuated REDs at concentrations near their average therapeutic plasma concentrations. γ-aminobutyric acid (GABA)ergic synaptic transmission-modulating ASDs (clobazam, midazolam, phenobarbital, stiripentol, tiagabine, and vigabatrin) attenuated REDs only at higher concentrations and, in some cases, prolonged RED durations. ASDs with other/mixed mechanisms of action (bumetanide, ethosuximide, felbamate, gabapentin, levetiracetam, topiramate, and valproate) and glutamate receptor antagonists weakly or incompletely inhibited RED frequency, increased RED duration, or had no significant effects.

Significance: Taken together, these data suggest that epileptiform activity recorded from the superficial layers of the mEC in slices obtained from KA-rats is differentially sensitive to existing ASDs. The different sensitivities of REDs to these ASDs may reflect persistent molecular, cellular, and/or network-level changes resulting from disease. These data are expected to serve as a foundation upon which future therapeutics may be differentiated and assessed for potentially translatable efficacy in patients with refractory epilepsy.

Keywords: antiepileptic drugs; brain slices; pharmacoresistance.

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Conflict of interest statement

Disclosure of conflicts of interest

KSW is a scientific advisor and receives stock options for Blackfynn, Inc. CSM is a scientific advisor and stockholder in Sea Pharmaceuticals, LLC. HSW has served as a consultant to Greenwich Pharmaceuticals and Bial Pharmaceuticals in the previous 12 months. HSW is also a scientific co-founder of NeuroAdjuvants, Inc., SLC, UT. None of the other authors have any conflict of interest to disclose.

Figures

Figure 1:
Figure 1:
Concentration-dependent inhibition of REDs by ezogabine (EZG). A) Representative traces of REDs recorded before (baseline) and in the presence of 100 µM EZG. B) Time courses for 100 µM EZG’s effects of RED duration (B1, green), frequency (B2, blue), and amplitude (B3, red). Dashed-line boxes from 20 to 40 minutes represent the duration of EZG exposure. Data points represent mean ± SEM for RED parameters in 1-minute bins. C) Concentration-dependent effects of EZG on RED duration (green), frequency (blue), and amplitude (red). Bars represent mean ± SEM of N slices (see Table 1) and * = p
Figure 2:
Figure 2:
Concentration-dependent inhibition of REDs by carbamazepine (CBZ). A) Representative traces of REDs recorded before (baseline) and in the presence of 30 µM CBZ. B) Time courses for 30 µM CBZ’s effects of RED duration (B1, green), frequency (B2, blue), and amplitude (B3, red). Dashed-line boxes from 20 to 40 minutes represent the duration of CBZ exposure. Data points represent mean ± SEM for RED parameters in 1-minute bins. C) Concentration-dependent effects of CBZ on RED duration (green), frequency (blue), and amplitude (red). Bars represent mean ± SEM of N slices (see Table 1) and * = p
Figure 3:
Figure 3:
Gabapentin (GBP) fails to affect REDs at any concentrations tested. A) Representative traces of REDs recorded before (baseline) and in the presence of 1 mM GBP. B) Time courses for 1 mM GBP’s effects of RED duration (B1, green), frequency (B2, blue), and amplitude (B3, red). Dashed-line boxes from 20 to 40 minutes represent the duration of GBP exposure. Data points represent mean ± SEM for RED parameters in 1-minute bins. C) Concentration-dependent effects of GBP on RED duration (green), frequency (blue), and amplitude (red). Bars represent mean ± SEM of N slices (see Table 1) and * = p
Figure 4:
Figure 4:
Topiramate (TPM) prolongs RED duration in a concentration-dependent manner. A) Representative traces of REDs recorded before (baseline) and in the presence of 100 µM TPM. B) Time courses for 100 µM TPM’s effects of RED duration (B1, green), frequency (B2, blue), and amplitude (B3, red). Dashed-line boxes from 20 to 40 minutes represent the duration of TPM exposure. Data points represent mean ± SEM for RED parameters in 1-minute bins. C) Concentration-dependent effects of TPM on RED duration (green), frequency (blue), and amplitude (red). Bars represent mean ± SEM of N slices (see Table 1) and * = p
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