Abstract
Epilepsy is a common neurological disorder characterized by naturally-occurring spontaneous recurrent seizures and comorbidities. Kindling has long been used to model epileptogenic mechanisms and to assess antiepileptic drugs. In particular, extended kindling can induce spontaneous recurrent seizures without gross brain lesions, as seen clinically. To date, the development of spontaneous recurrent seizures following extended kindling, and the effect of the antiepileptic drugs on these seizures are not well understood. In the present study we aim to develop a mouse model of extended hippocampal kindling for the first time. Once established, we plan to evaluate the effect of three different antiepileptic drugs on the development of the extended-hippocampal-kindled-induced spontaneous recurrent seizures. Male C57 black mice were used for chronic hippocampal stimulations or handling manipulations (twice daily for up to 70 days). Subsequently, animals underwent continuous video/EEG monitoring for seizure detection. Spontaneous recurrent seizures were consistently observed in extended kindled mice but no seizures were detected in the control animals. The aforementioned seizures were generalized events characterized by hippocampal ictal discharges and concurrent motor seizures. Incidence and severity of the seizures was relatively stable while monitored over a few months after termination of the hippocampal stimulation. Three antiepileptic drugs with distinct action mechanisms were tested: phenytoin, lorazepam and levetiracetam. They were applied via intra-peritoneal injections at anticonvulsive doses and their effects on the spontaneous recurrent seizures were analyzed 10–12 h post-injection. Phenytoin (25 mg/kg) and levetiracetam (400 mg/kg) abolished the spontaneous recurrent seizures. Lorazepam (1.5 mg/kg) decreased motor seizure severity but did not reduce the incidence and duration of corresponding hippocampal discharges, implicating its inhibitory effects on seizure spread. No gross brain lesions were observed in a set of extended hippocampal kindled mice submitted to histological evaluation. All these data suggests that our model could be considered as a novel mouse model of extended hippocampal kindling. Some limitations remain to be considered.
Highlights
Epilepsy is a common neurological disorder characterized by naturally-occurring spontaneous recurrent seizures (SRS) and comorbidities
The 14 “kindled” mice were used for extended kindling
We aimed to develop a mouse model of extended hippocampal kindling with a particular focus on antiepileptic drugs (AEDs) effects in the present study
Summary
Epilepsy is a common neurological disorder characterized by naturally-occurring spontaneous recurrent seizures (SRS) and comorbidities. SRS development following extended amygdala kindling is generally associated with a loss of subgroups of hippocampal GABAergic interneurons in dentate gyrus-hilar areas (Sayin et al, 2003; Brandt et al, 2004) rather than gross brain lesions as seen in different status epilepticus models (Dudek and Staley, 2017; Gorter and van Vliet, 2017; Henshall, 2017; Kelly and Coulter, 2017). This way, extended kindling may help model the genesis of SRS without a major brain pathology as usually seen in TLE patients (Ferlazzo et al, 2016). SRS following extended kindling and the effect of different AEDs on such seizures are still not well understood
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