Table 1.
Experimental design of the animal antiseizure models.
| Animal Model | Study | Species | Route | Drugs | Pretreatment | Test | n/group | Observation Interval | Endpoints |
|---|---|---|---|---|---|---|---|---|---|
| MES | NINDS | CF-1 Mice | IP | 0.5% MC, CBM; YKP3090; YKP1983 | 0.25 h | 50 mA, 60 Hz, 0.2 s corneal electrodes | 8 | Within 5 s of MES | Full tonic extension of hindlimbs |
| A | ICR Mice | IP/PO | 30%PEG400, CBM, PHT | 0.5 h IP 1.0 h PO |
50 mA, 60 Hz, 0.2 s corneal electrodes | 8 | Within 5 s of MES | Full tonic extension of hindlimbs | |
| B | CF-1 Mice | IP | 30%PEG400, CBM, VPA | 0.5 h | 50 mA, 60 Hz, 0.2 s corneal electrodes | 8–10 | Within 5 s of MES | Full tonic extension of hindlimbs | |
| NINDS | SD Rats | IP/PO | 0.5% MC, CBM, YKP3090; YKP1983 | 4, 0.5, 2 h IP 1 h PO |
150 mA, 60 Hz, 0.2 s corneal electrodes | 8 | Within 5 s of MES | Full extension of tonic hindlimbs | |
| C | SD Rats | PO | 30%PEG400, CBM, CBZ | 1 h | 150 mA, 60 Hz, 0.2 s corneal electrodes | 8 | Within 5 s of MES | Full extension of tonic hindlimbs | |
| D | SD Rats | PO | 0.5% MC, CBM (3 batches), CBZ | 1 h | 180 mA, 60 Hz, 0.2 s corneal electrodes | 8 | Within 5 s of MES | Full extension of tonic hindlimbs | |
| MES tolerance | E | CF-1 Mice | IP | 30%PEG400, CBM | 4 days saline → CBM → 0.5 h 5 days CBM →0.5 h |
50 mA, 60 Hz, 0.2 s corneal electrodes | 8 | Within 5 s of MES | Full extension of tonic hindlimbs |
| 6 Hz | NINDS | CF-1 Mice | IP | 0.5% MC, CBM | 0.25 h | 22, 32, or 44 mA, 60 Hz, 0.2 s corneal electrodes | 8 | NA | Minimal clonic seizures with stereotyped automastic behaviors |
| Hippocampal kindling | NINDS | SD rat with bipolar electrodes in ventral hippocampus | IP | 0.5% MC, CBM; YKP3090; YKP1983 | Rats kindled to Stage 5 with 5 stimulus days (2 days apart) of 50 Hz 10 s 1 ms biphasic 200 μA every 30 min for 6 h On treatment day: 15 min |
20 μA + 10 μA every 1–2 min until after discharge duration | 6 | 0, 0.25, 0.75, 1.25, 1.75, 2.25 h | Racine seizure score S1-5, after discharge duration |
| After-discharge threshold | ADT | SD Rat with bipolar electrodes in ventral hippocampus | IP | 0.5% MC, CBM | Rats kindled to Stage 5 with 5 stimulus days (2 days apart) of 50 Hz 10 s 1 ms biphasic 200 μA every 30 min for 6 h On treatment day: 15 min |
20 μA + 10 μA every 1–2 min until after discharge duration | 6 | 0, 0.25, 1, 2 4 h | Racine seizure score S1-5, after discharged threshold, after discharge duration |
| PTZ | NINDS | CF-1 Mice | IP/PO | 0.5% MC, CBM, YKP3090; YKP1983 | 0.25 h | 85 mg/kg PTZ SC | 8 | 30 min | Repeated clonic seizures (>3 s) |
| F | ICR Mice | IP/PO | 30%PEG400, CBM, ESM | 0.5 h | 95.2 mg/kg PTZ SC | 8 | 30 min | Generalized clonus; repeated clonic seizures (>3 s) | |
| G | CF-1 Mice | IP | 30%PEG400, CBM, VPA | 0.5 h | 85 mg/kg PTZ SC | 8–10 | 30 min | Generalized clonus; repeated clonic seizures (>3 s); tonic extension | |
| NINDS | SD Rats | IP/PO | 0.5% MC, CBM, YKP3090, YKP1983 | 4, 0.5, 0.5 h IP 1 h PO |
56.4 mg/kg (Simonsen); 68 mg/kg (Charles River) PTZ SC | 8 | 30 min | Repeated clonic seizures (>3 s); tonic extension | |
| H | SD Rats | PO | 30%PEG400, CBM | 1 h | 105.8 mg/kg PTZ SC | 8 | 30 min | Generalized clonus; repeated clonic seizures (>3 s) | |
| I | SD Rats | PO | 30%PEG400, CBM, VPA | 1 h | 70 mg/kg PTZ SC | 4–8 | 30 min | Generalized clonus; repeated clonic seizures (>3 s) | |
| IV PTZ | NINDS | CF-1 Mice | IP | 0.5% MC, CBM, YKP3090, YKP1983 | 0.25 h | 0.34 mL/min 0.5% Metrazol IV in heparinized saline | 10 | NA | Time (s) first twitch; time (s) onset of sustained clonus |
| Bic | NINDS | CF-1 Mice | IP | 0.5% MC, CBM | 0.25 h | 2.7 mg/kg Bic SC | 8 | 30 min | Repeated clonic seizures (>3 s) |
| J | ICR Mice | IP | 30%PEG400, CBM, VPA | 0.5 h | 3.4 mg/kg Bic SC | 8 | 30 min | Generalized clonus; repeated clonic seizures (>3 s) | |
| K | CF-1 Mice | IP | 30%PEG400, CBM, DZP | 0.5 h | 3.5 mg/kg Bic SC | 7–10 | 30 min | Clonic seizures (hopping; LORR >3 s) | |
| Pic | NINDS | CF-1 Mice | IP | 0.5% MC, CBM | 0.25 h | 2.5 mg/kg Pic SC | 8 | 30 min | Repeated clonic seizures (>3 s) |
| L | ICR Mice | IP | 30%PEG400, CBM, VPA | 0.5 h | 4.5 mg/kg Pic SC | 8 | 45 min | Generalized clonus; repeated clonic seizures (>3 s) | |
| GAERS | M | GAERS Rats with 4 mono-polar electrodes frontal and parietal cortices | IP | 30%PEG400, CBM, VPA | 10 min | 1 h habituation; 20-min EEG baseline; 10 min post dose |
9 | 10 min–90 min post-dose | Number and cumulated duration of SWDs |
ADT, afterdischarge threshold; CBM, cenobamate; CBZ, carbamazepine; DZP, diazepam; EEG, electroencephalogram; ESM, ethosuximide; GAERS, Genetic Absence Epilepsy Rate from Strasbourg; h, hours; IP, intraperitoneal; IV, intravenous; LORR, loss of righting reflex; MC; methylcellulose; MES, maximal electroshock seizure; NA, not available. NINDS, National Institute of Neurological Disorders and Stroke; PEG, polyethylene glycol; PHT, phenytoin; PO, oral; PTZ, pentylenetetrazol/metrazole; s, seconds; SC, subcutaneous; SD, Sprague Dawley; SWD, spike-and-wave discharge; VPA, valproic acid/valproate.