Abstract/Summary

Epilepsy is a chronic neurological disease characterised by recurrent seizures, premature mortality and several associated comorbidities such as motor disorder, anxiety, depression, social deficits and cognitive impairment. Here, the effect of cannabidiol (CBD) in three different preclinical models of epilepsy was investigated. First, the effect of 9-weeks oral CBD administration (200 mg/kg/day) on seizures, motor function, gait and cognition in a reduced intensity status epilepticus induced spontaneous recurrent seizures (RISE-SRS) rat model of temporal lobe epilepsy (TLE) was evaluated. Subsequently, the effect of long-term CBD administration (100 mg/kg, twice daily s.c. injections from postnatal day 8 (P8) to 25/death) on survivability and a number of welfare parameters such as natural activity, reflex/response to touch, total neonatal welfare, orbital tightening and body condition in the Scn1a-/- mouse model was investigated. Finally, the effect of chronic CBD administration (100 mg/kg, twice daily s.c. injections from P8 to 52/death) on premature mortality and comorbidities such as motor dysfunction, social deficits, anxiety, depression and cognitive impairment in the Scn1a+/- mouse model of Dravet syndrome was assessed. I demonstrated for the first time that chronic CBD treatment improved seizures, motor function and cognition without producing any adverse effect on gait in RISE-SRS rat model of TLE. Further, I showed that CBD treatment extended survivability and improved the neonatal welfare parameters in the Scn1a-/- mouse model. Moreover, I established the novel finding that chronic CBD-treatment prevented premature mortality and improved the comorbidities associated with the Scn1a+/- mouse model of Dravet syndrome. Although the anticonvulsant property of CBD has been shown in animal models of seizures, I am the first to demonstrate that CBD has disease modifying potential, and improves seizures, survivability and comorbidities associated with preclinical models of epilepsy. Notably, this project formed a core part in the development and US-FDA approval of Epidiolex® (GW Pharmaceuticals) in 2018.