Effect of carbamazepine on spontaneous recurrent seizures recorded from the dentate gyrus in rats with kainate‐induced epilepsy

Abstract

Summary Objective Animal models of chronic epilepsy with spontaneous recurrent seizures (SRSs) may be useful in the discovery and mechanistic analyses of antiseizure drugs (ASDs). Carbamazepine (CBZ), a widely used ASD with a well‐defined mechanism, was analyzed in this proof‐of‐principle study to determine how a traditional ASD affects the properties of SRSs. Methods The effects of CBZ on electrographic SRSs recorded from the dentate gyrus were studied in freely behaving rats using a repeated, low‐dose kainate model of acquired epilepsy with a repeated‐measures, crossover protocol. Results Almost all seizure durations were >20 seconds. Both seizure likelihood and duration appeared to be similar between 1 and 8 hours after individual CBZ injections. CBZ‐induced decreases in seizure frequency were not significant at 10 mg/kg; however, at 30 mg/kg, seizure frequency was significantly reduced for convulsive but not nonconvulsive seizures. At 100 mg/kg, CBZ strongly suppressed both convulsive and nonconvulsive seizures. Although CBZ had a dose‐dependent effect on seizure frequency, CBZ did not affect seizure duration at any dose. The preceding interictal interval did not affect seizure duration; however, at 30 mg/kg CBZ, nearly all seizures were nonconvulsive when the interictal interval was <30 minutes (ie, during clusters). Significance Increased doses of CBZ (10‐100 mg/kg) suppressed the frequency but not the duration of convulsive and nonconvulsive seizures in the repeated, low‐dose kainate model. The repeated‐measures, crossover protocol, which requires relatively few animals and compensates for progressive increases in seizure frequency during epileptogenesis after status epilepticus, allowed quantitative analyses of clinically relevant and translatable properties of SRSs.

Relationship between Delta Rhythm, Seizure Occurrence and Allopregnanolone Hippocampal Levels in Epileptic Rats Exposed to the Rebound Effect

“…In additional experiments, carbamazepine (30 mg/kg) significantly reduced the frequency of convulsive SRSs without affecting nonconvulsive SRSs recorded in the dentate gyrus. Carbamazepine adequately suppressed the frequency of all SRSs only at 100 mg/kg, while duration remained unchanged also at this dose [21]. Thus, LEV in our animals produced effects comparable to those of the other AEDs.…”

“…To this aim, we adopted the systemic KA model of chronic epilepsy [17], by introducing substantial differences with respect to most of the published research on testing AEDs in the same animal model. With few exceptions [21], the previous experiments did not address the frequency of nonconvulsive SRSs or the overall seizure duration, but only the frequency of convulsive SRSs was monitored by behavioral analysis [22]. Moreover, topiramate, carbamazepine, and carisbamate, but not LEV were the examined AEDs after the systemic injection of KA [23][24][25].…”

The Positive Allosteric Modulator ofα2/3-Containing GABAAReceptors, KRM-II-81, Is Active in Pharmaco-Resistant Models of Epilepsy and Reduces Hyperexcitability after Traumatic Brain Injury

“…KRM-II-81 was also active in the lamotrigine-resistant kindling model, predicting positive impact on pharmaco-resistant epilepsy (Srivastava et al, 2013;Wilcox et al, 2013;Barker-Haliski et al, 2017). Chronic spontaneous recurrent seizures in epilepsy were modeled in the present study with a repeated low-dose kainate model in rats (Barker-Haliski et al, 2017;Grabenstatter and Dudek, 2019). Clinically relevant measures of human epilepsies with chronic recurrent spontaneous seizures were suppressed by KRM-II-81.…”

“…The procedure results in the occurrence, weeks later, of recurrent spontaneous focal and generalized seizures . The methods are as described previously (Barker-Haliski et al, 2017;Grabenstatter and Dudek, 2019). Briefly, male Sprague-Dawley rats were injected with 7.5 mg/kg kainic acid, i.p., at 0 hour, 1 hour, and every subsequent half-hour (up to 4 hours), or until the animal displayed two Racine stage 5 seizures and was then given 3 ml of Ringers solution to prevent dehydration.…”

“…This model enables the monitoring of spontaneous recurrent seizures and clinically relevant measures of epilepsy. It is used in late stages of antiepileptic drug screening (Barker-Haliski et al, 2017;Grabenstatter and Dudek, 2019) to create clinically relevant measures of epilepsies for antiepileptic drug differentiation (West et al, 2018).…”