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Recurrent epileptiform discharges in the medial entorhinal cortex of kainate‐treated rats are differentially sensitive to antiseizure drugs
Author(s) -
West Peter J.,
Saunders Gerald W.,
Billingsley Peggy,
Smith Misty D.,
White H. Steve,
Metcalf Cameron S.,
Wilcox Karen S.
Publication year - 2018
Publication title -
epilepsia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.687
H-Index - 191
eISSN - 1528-1167
pISSN - 0013-9580
DOI - 10.1111/epi.14563
Subject(s) - ethosuximide , lamotrigine , vigabatrin , pharmacology , zonisamide , carbamazepine , epilepsy , clobazam , levetiracetam , anticonvulsant , status epilepticus , tiagabine , lacosamide , epileptogenesis , chemistry , kainate receptor , valproic acid , phenytoin , anesthesia , medicine , glutamate receptor , neuroscience , ampa receptor , psychology , topiramate , receptor
Summary Objective Approximately 30% of patients with epilepsy are refractory to existing antiseizure drugs ( ASD s). 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 ASD s on recurrent epileptiform discharges ( RED s) 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 RED s were recorded from the superficial layers. 6‐cyano‐7‐nitroquinoxaline‐2,3‐dione , (2 R )‐amino‐5‐phosphonovaleric acid, tetrodotoxin , or ASD s 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 RED s at concentrations near their average therapeutic plasma concentrations. γ‐aminobutyric acid ( GABA) ergic synaptic transmission–modulating ASD s (clobazam, midazolam, phenobarbital, stiripentol, tiagabine, and vigabatrin) attenuated RED s only at higher concentrations and, in some cases, prolonged RED durations. ASD s 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 ASD s. The different sensitivities of RED s to these ASD s 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.