Modulation of the endocannabinoid system in the GAERS rat model of absence epilepsy.

Absence seizures are a form of epilepsy that account for approximately 10% of childhood seizures. Children suffering from absence seizures will experience short (10-20 sec) lapses in awareness. Seizures may occur up to 100 times per day. Children experiencing absence seizures have difficulty learning, misbehave more often, and/or have difficulty socializing. Existing therapeutic options successfully manage absence seizures in approximately 2/3 of patients. There is a rapidly growing interest in the usefulness of cannabinoids to treat childhood epilepsies. The major mediator of cannabinoid effects in the brain is the type 1 cannabinoid receptor (CB1R). CB1R is activated by ∆9-tetrahydrocannabinol and the body’s own cannabinoids. Most cannabinoids act to turn CB1R on directly, but these produce intoxicating effects. Positive allosteric modulators (PAMs) work by increasing CB1R’s response to the body’s own cannabinoids, but cannot directly activate CB1R and, because of this, are not intoxicating. The purpose of this study is to test CB1R PAMs for their usefulness to treat absence seizures. This will be done by (1) screening PAMs in cultured cells for high efficacy and potency at CB1R, and (2) selecting the most efficacious PAMs from this screen to test in a rat model of absence epilepsy. We have identified a lead compound – GAT211 – that reduces seizure duration and anxiety in our rat model. New PAMs based on GAT211 with improved efficacy may produce medicines for the treatment absence seizures and other forms of pediatric epilepsy for which there is a clinically unmet need for children in Saskatchewan.