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Recurrent epileptiform discharges in the medial entorhinal cortex of kainate-treated rats are differentially sensitive to antiseizure drugs.
Epilepsia 2018; 59(11):2035-2048E

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.

Authors+Show Affiliations

Department of Pharmacology and Toxicology, University of Utah, Salt Lake City, Utah. Epilepsy Therapy Screening Program (ETSP) Contract Site, University of Utah, Salt Lake City, Utah. Interdepartmental Neuroscience Program, University of Utah, Salt Lake City, Utah.Epilepsy Therapy Screening Program (ETSP) Contract Site, University of Utah, Salt Lake City, Utah.Epilepsy Therapy Screening Program (ETSP) Contract Site, University of Utah, Salt Lake City, Utah.Department of Pharmacology and Toxicology, University of Utah, Salt Lake City, Utah. Epilepsy Therapy Screening Program (ETSP) Contract Site, University of Utah, Salt Lake City, Utah. School of Dentistry, University of Utah, Salt Lake City, Utah.Department of Pharmacy, University of Washington, Seattle, Washington.Department of Pharmacology and Toxicology, University of Utah, Salt Lake City, Utah. Epilepsy Therapy Screening Program (ETSP) Contract Site, University of Utah, Salt Lake City, Utah.Department of Pharmacology and Toxicology, University of Utah, Salt Lake City, Utah. Epilepsy Therapy Screening Program (ETSP) Contract Site, University of Utah, Salt Lake City, Utah. Interdepartmental Neuroscience Program, University of Utah, Salt Lake City, Utah.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural

Language

eng

PubMed ID

30328622

Citation

West, Peter J., et al. "Recurrent Epileptiform Discharges in the Medial Entorhinal Cortex of Kainate-treated Rats Are Differentially Sensitive to Antiseizure Drugs." Epilepsia, vol. 59, no. 11, 2018, pp. 2035-2048.
West PJ, Saunders GW, Billingsley P, et al. Recurrent epileptiform discharges in the medial entorhinal cortex of kainate-treated rats are differentially sensitive to antiseizure drugs. Epilepsia. 2018;59(11):2035-2048.
West, P. J., Saunders, G. W., Billingsley, P., Smith, M. D., White, H. S., Metcalf, C. S., & Wilcox, K. S. (2018). Recurrent epileptiform discharges in the medial entorhinal cortex of kainate-treated rats are differentially sensitive to antiseizure drugs. Epilepsia, 59(11), pp. 2035-2048. doi:10.1111/epi.14563.
West PJ, et al. Recurrent Epileptiform Discharges in the Medial Entorhinal Cortex of Kainate-treated Rats Are Differentially Sensitive to Antiseizure Drugs. Epilepsia. 2018;59(11):2035-2048. PubMed PMID: 30328622.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Recurrent epileptiform discharges in the medial entorhinal cortex of kainate-treated rats are differentially sensitive to antiseizure drugs. AU - West,Peter J, AU - Saunders,Gerald W, AU - Billingsley,Peggy, AU - Smith,Misty D, AU - White,H Steve, AU - Metcalf,Cameron S, AU - Wilcox,Karen S, Y1 - 2018/10/17/ PY - 2018/06/27/received PY - 2018/08/17/revised PY - 2018/08/17/accepted PY - 2018/10/18/pubmed PY - 2019/4/5/medline PY - 2018/10/18/entrez KW - antiepileptic drugs KW - brain slices KW - pharmacoresistance SP - 2035 EP - 2048 JF - Epilepsia JO - Epilepsia VL - 59 IS - 11 N2 - 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. SN - 1528-1167 UR - https://www.unboundmedicine.com/medline/citation/30328622/Recurrent_epileptiform_discharges_in_the_medial_entorhinal_cortex_of_kainate-treated_rats_are_differentially_sensitive_to_antiseizure_drugs L2 - https://doi.org/10.1111/epi.14563 DB - PRIME DP - Unbound Medicine ER -