TY - JOUR
T1 - Pharmacoresponsiveness of spontaneous recurrent seizures and the comorbid sleep disorder of epileptic Kcna1-null mice
AU - Deodhar, Malavika
AU - Matthews, Stephanie A.
AU - Thomas, Brittany
AU - Adamian, Leena
AU - Mattes, Sarah
AU - Wells, Tabitha
AU - Zieba, Brianna
AU - Simeone, Kristina A.
AU - Simeone, Timothy A.
N1 - Funding Information:
This work was supported by Citizens United for Research in Epilepsy Foundation (TAS), NIH NS085389 (TAS), NIH NS072179 (KAS) and NIH NS111389 (KAS). The project described was also supported by the National Center for Research Resources grant G20RR024001 . The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the National Institutes of Health .
Publisher Copyright:
© 2021
PY - 2021/12/15
Y1 - 2021/12/15
N2 - Drug resistant epilepsy affects ∼30% of people with epilepsy and is associated with epilepsy syndromes with frequent and multiple types of seizures, lesions or cytoarchitectural abnormalities, increased risk of mortality and comorbidities such as cognitive impairment and sleep disorders. A limitation of current preclinical models is that spontaneous seizures with comorbidities take time to induce and test, thus making them low-throughput. Kcna1-null mice exhibit all the characteristics of drug resistant epilepsy with spontaneous seizures and comorbidities occurring naturally; thus, we aimed to determine whether they also demonstrate pharmacoresistanct seizures and the impact of medications on their sleep disorder comorbidity. In this exploratory study, Kcna1-null mice were treated with one of four conventional antiseizure medications, carbamazepine, levetiracetam, phenytoin, and phenobarbital using a moderate throughput protocol (vehicle for 2 days followed by 2 days of treatment with high therapeutic doses selected based on published data in the 6 Hz model of pharmacoresistant seizures). Spontaneous recurrent seizures and vigilance states were recorded with video-EEG/EMG. Carbamazepine, levetiracetam and phenytoin had partial efficacy (67%, 75% and 33% were seizure free, respectively), whereas phenobarbital was fully efficacious and conferred seizure freedom to all mice. Thus, seizures of Kcna1-null mice appear to be resistant to three of the drugs tested. Levetiracetam failed to affect sleep architecture, carbamazepine and phenytoin had moderate effects, and phenobarbital, as predicted, restored sleep architecture. Data suggest Kcna1-null mice may be a moderate throughput model of drug resistant epilepsy useful in determining mechanisms of pharmacoresistance and testing novel therapeutic strategies.
AB - Drug resistant epilepsy affects ∼30% of people with epilepsy and is associated with epilepsy syndromes with frequent and multiple types of seizures, lesions or cytoarchitectural abnormalities, increased risk of mortality and comorbidities such as cognitive impairment and sleep disorders. A limitation of current preclinical models is that spontaneous seizures with comorbidities take time to induce and test, thus making them low-throughput. Kcna1-null mice exhibit all the characteristics of drug resistant epilepsy with spontaneous seizures and comorbidities occurring naturally; thus, we aimed to determine whether they also demonstrate pharmacoresistanct seizures and the impact of medications on their sleep disorder comorbidity. In this exploratory study, Kcna1-null mice were treated with one of four conventional antiseizure medications, carbamazepine, levetiracetam, phenytoin, and phenobarbital using a moderate throughput protocol (vehicle for 2 days followed by 2 days of treatment with high therapeutic doses selected based on published data in the 6 Hz model of pharmacoresistant seizures). Spontaneous recurrent seizures and vigilance states were recorded with video-EEG/EMG. Carbamazepine, levetiracetam and phenytoin had partial efficacy (67%, 75% and 33% were seizure free, respectively), whereas phenobarbital was fully efficacious and conferred seizure freedom to all mice. Thus, seizures of Kcna1-null mice appear to be resistant to three of the drugs tested. Levetiracetam failed to affect sleep architecture, carbamazepine and phenytoin had moderate effects, and phenobarbital, as predicted, restored sleep architecture. Data suggest Kcna1-null mice may be a moderate throughput model of drug resistant epilepsy useful in determining mechanisms of pharmacoresistance and testing novel therapeutic strategies.
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U2 - 10.1016/j.ejphar.2021.174656
DO - 10.1016/j.ejphar.2021.174656
M3 - Article
C2 - 34838797
AN - SCOPUS:85120409958
VL - 913
JO - European Journal of Pharmacology
JF - European Journal of Pharmacology
SN - 0014-2999
M1 - 174656
ER -