Abstracts

Rationale: Dravet syndrome is a severe, genetic form of pediatric epilepsy, which is associated with several comorbidities such as anxiety, depression, autism, motor abnormalities and memory deficits. Currently available anti-epileptic treatments rarely offer satisfactory control of seizures and these comorbidities. Here, we investigated the efficacy of pure cannabidiol (CBD) on survivability in a mouse model of Dravet syndrome. Additionally, the impact of CBD on associated behavioral comorbidities was assessed. Methods: Scn1a+/- mice were subcutaneously injected with highly purified CBD (GW Research Ltd; 100 mg/kg; n=12) or its vehicle (ethanol: kolliphor®: 0.9% saline=2:1:17; n=29) twice daily from postnatal day 8 (P8) onwards until P52 or death (whichever was earlier). An age-matched vehicle-treated group of wild type (WT) animals was used as a control (n=11). Mice were video monitored for the assessment of seizure-related mortality and, from P35 onwards, animals were assessed for alterations in their social (social interaction task), depressive-like (sucrose preference test) and anxiety-like (elevated plus maze test, EPM) behaviors and memory function (radial arm maze test). Given that a significant number of deaths were predicted to occur between P20-P27 in vehicle-treated Scn1a+/- a larger initial group size was utilised to obtain a minimum n=10 animals/group for behavioral assessment at P35. Results: CBD significantly (p< 0.05) increased the survivability of Scn1a^+/- mice compared to their vehicle-treated counterparts. Approximately 66% of Scn1a^+/- vehicle-treated animals died (median survivability 24 days) of tonic-clonic seizure before completion of the study, compared to only 17% in Scn1a^+/- CBD-treated group (p< 0.05). The vehicle-treated Scn1a^+/- group exhibited reduced social interaction (p< 0.001), sucrose preference (p< 0.01) and time spent in open arms of EPM (p< 0.05) along with impaired working (p< 0.01) and reference memory (p< 0.0001) when compared to the vehicle-treated WT group. However, CBD significantly increased social interaction time (p< 0.001), sucrose preference (p< 0.05) and time spent in open arms of EPM (p< 0.05) in Scn1a^+/- mice when compared to vehicle-treated Scn1a^+/- mice, indicating that CBD treatment improved social behavior and reduced both depressive-like and anxiety-like behaviors. CBD also improved working (p< 0.01) and reference memory (p< 0.0001) performance in Scn1a^+/- mice compared to vehicle-treated Scn1a^+/- mice. Importantly, no significant differences were seen for these parameters between vehicle-treated WT and CBD-treated Scn1a^+/- mice suggesting that CBD treatment restores the deficits induced by the Scn1a^+/- genotype.  Conclusions: This study demonstrated that CBD treatment increased survivability, improved social behavior, and memory function and reduced anxiety-like and depressive-like behaviors in Scn1a^+/- mice. This is the first study to show a beneficial effect of CBD on the survivability and comorbidities of Dravet syndrome mice following long-term treatment. Funding: GW Research Ltd and the University of Reading