Benzodiazepine Resistant Lithium-Pilocarpine Status Epilepticus Model (rat)

While most seizures are often short duration events that resolve spontaneously, status epilepticus (SE) events are characterized by continuous epileptic seizures or a series of seizures lasting longer than 30 minutes without full recovery of consciousness between seizures. Typically, treatment of SE requires emergency room intervention with either diazepam or lorazepam, immediately followed by phenytoin or phenobarbital. However, up to 15% of SE episodes can be refractory to these conventional therapies, thus identifying novel treatments that can treat refractory SE, i.e. benzodiazepine-resistant SE, is of critical value to the clinical management of SE. The lithium-pilocarpine induced SE in rats is a commonly used animal model to identify novel treatments that can stop seizures when administered 30 minutes after the onset of SE because by this time point rats develop resistance to benzodiazepines (Jones et al., 2002). To induce SE, Sprague Dawley CD rats (n = 8 per group; 100-150 g) are injected intraperitoneally (IP) with lithium chloride (127 mg/kg) 20 - 24 hours prior to the administration of pilocarpine (50 mg/kg; IP). Thirty minutes following the first behavioral stage 3 seizure on the Racine scale rats receive a dose of the investigational compound based on MES or 6Hz rat model results and/or other dosing data provided by the participant. The ability of the compound to attenuate benzodiazepine-resistant convulsive SE is monitored for the next 4 hours, and measurements include the time of cessation for behavioral convulsive SE, Racine score, 24 hours survival rate, and animal weight. At the time of testing, a blinded observer confirms behavioral observations.