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(Abst. 3.026), 2014

USE OF ETHOSUXIMIDE TO IMPROVE OUTCOME IN THE KAINIC ACID MODEL OF TEMPORAL LOBE EPILEPSY
Authors: Sloka Iyengar, John LaFrancois and Helen Scharfman
Content: Rationale: Animal models that simulate epilepsy are essential for identification of new anti-seizure drugs. A common animal model of temporal lobe epilepsy uses kainic acid (KA) to induce status epilepticus (SE), and ultimately, spontaneous, recurrent seizures (epilepsy). Transgenic mice on a C57bL6/J background are commonly used, but this strain poses problems: variability and mortality. Hence, the same dose of KA can produce no SE or severe convulsions resulting in mortality, even when administered under the same conditions. Because severe seizures elicited by KA typically involve the brainstem (characterized by running and bouncing seizures), we hypothesized that a drug that decreased brainstem seizures would decrease variability and mortality. Methods: Adult (9-13 weeks-old), male C57bl/6J mice (n=32; Jackson Laboratories) were anesthetized and implanted stereotaxically with 4 electrodes: epidural screws over the left frontal cortex and right occipital cortex, and twisted bipolar electrodes in each dorsal hippocampus (Pinnacle Technologies). After ≥ 1 week for recovery, mice were placed in a new cage where their pin connector was attached to a cable with a commutator (Pinnacle Technologies) to allow freedom of movement. Baseline recordings were made for >10 min and drug(s) were administered. We used a dose of KA that that elicited severe seizures (20 mg/kg; Milestone Pharmatech). One group of mice was administered KA in the absence of pretreatment (n=10). The second group was administered ethosuximide (150 mg/kg) followed 30 min later by KA (n=15), and the third group of mice was injected with vehicle (20% ethanol in phosphate buffered saline) followed 30 min later by KA (n=7). Video-EEG was acquired at 500 Hz (Pinnacle) and analyzed offline (Acqknowledge; Biopac Systems). Results: Administration of KA without pretreatment led to variable outcomes, with few seizures in 3/10 mice, SE in 4/10 mice, and mortality (3/10 mice). In mice pretreated with ethosuximide, the incidence of SE was higher (13/15 mice; Fisher's Exact test, p=0.009) and there was no mortality (0/15 mice; Fisher's Exact test; p=0.046). There were no differences between ethosuximide and vehicle pretreated- mice in the following parameters: incidence of SE, mortality, seizure latency, duration and number of seizures (Student's t-test; p<0.05 for all measurements). Interestingly, EEG analysis revealed that the onset of the first seizure was more likely to be in the hippocampus after ethosuximide pretreatment compared to vehicle pretreatment (Fisher's exact test; p=0.030). Conclusions: Administration of ethosuximide before KA in adult C57bl6/J mice reduced variability in response to 20 mg/kg KA. These results are consistent with a role of ethosuximide to decrease seizure activity in brainstem circuits, permitting seizure activity in forebrain structures such as hippocampus to become dominant. Hence, ethosuximide pretreatment could improve outcome when the C57bl/6J strain is used in SE models of temporal lobe epilepsy.