Abstracts

Rationale: The intrahippocampal kainate mouse model of mesial temporal lobe epilepsy features focal, mainly non-convulsive, difficult-to treat seizures with dispersion of granule cells in the dentate gyrus and neurodegeneration of CA1 and CA3 regions in the hippocampus. Herewith, the model reflects well the drug-resistant focal-onset seizures described for patients diagnosed with mesial temporal-lobe epilepsy and hippocampal sclerosis. Methods: Kainate (KA; 50 nL of 20 or 30 mM solution) was intracranially administered in the dorsal hippocampus (AP: -1.8, ML: -1.5, DV: -1.8 from bregma) of adult male C57BL/6J mice. Subsequently mice were equipped with a HD-X02 implant (Data Science International) for electroencephalographic (EEG), and body temperature recording by telemetry. One lead of the telemetry implant was connected to a stereotaxically placed intrahippocampal EEG electrode and two leads were placed contralaterally on the surface of the cortex for cortical EEG recording. Following KA-induced status epilepticus, spontaneous seizures and body temperature (BT) were recorded in mice that were either left untreated or that were orally treated with different anti-epileptics. The number of seizures (NS) and the cumulated duration of seizures (DS) were analyzed (Ponemah and Neuroscore, Data Science International). Results: During KA-induced status epilepticus, mice presented with non-convulsive and convulsive seizures. Mice administered with KA 20 mM (n = 8) or 30 mM (n = 7) showed stable seizure activity in week 7 or 8 after hippocampal administration with 47+-1 (20 mM) or 52+-2 (30 mM) seizures per hour for a cumulated duration of seizures of 468+-19 s (20 mM) or 520+-15 s (30 mM). In week 9 or 10 post KA administration, number of seizures per hour were 47+-1 (20 mM) or 52+-2 (30 mM) and cumulated duration of seizure per hour were 463+-12 s (20 mM) or 470+-10 s (30 mM). Seizure activity during the 12h-dark phase was similar to that during 12h-light phase (20 mM - week 9, NS: dark 535+-59, light 587+-54, p = 0.76; 30 mM - week 10, NS: dark 662+-128, light 576+-92, p = 0.38). The anticonvulsant drug tiagabine at 1.2 mg/kg reduced the number of seizures and the cumulated duration of seizures in comparison to baseline (NS: -38+-14, p = 0.013; DS: -412+-110 s, p = 0.003, n = 6) but retigabine at 30 mg/kg did not (NS: -6+-13, p = 0.97; DS: -114+-151 s, p = 0.92, n = 5). Upon closer observation we noticed that retigabine (30 mg/kg) also induced a pronounced decrease of body temperature in a subset of mice (-2.7+-0.5°C to 34.5+-0.2°C, p = 0.002, n = 2). The very same mice showed surprisingly low seizure activity (NS: -36+-14, p = 0.46). For mice where retigabine did not change the body temperature (-0.82+-0.2°C to 37.1+-0.2°C, p = 0.27; n = 3), seizure activity was not reduced (NS: 13+-2, p = 0.80). Conclusions: Intrahippocampal KA injections led to a stable 24h seizure frequency 7 weeks after the induction of the status epilepticus in freely moving mice implanted with telemetry for continuous EEG recording. Seizure activity was significantly reduced by tiagabine. Hypothermia, which was observed in some mice after retigabine administration was associated with reduced seizure activity. Thus, it might become a confounding factor in the interpretation of putative antiepileptic efficacy of novel drugs. Funding: No funding