Abstracts

Rationale: Sudden unexpected death in epilepsy (SUDEP) is increasingly recognized as a major concern for patients with epilepsy, but there are no treatments currently approved to prevent this disastrous epilepsy outcome. Cannabidiol is an FDA-approved treatment for specific forms of epilepsy, including Dravet syndrome. Development of preventative treatments for SUDEP requires initial testing of agents in SUDEP animal models. A widely-used SUDEP model is the primed DBA/1 mouse, which exhibits audiogenic seizures (AGSz) that invariably lead to sudden death following the seizure. Death in these mice is mediated by respiratory arrest following a seizure, which is also the most commonly observed cause of death in SUDEP patients. The present study evaluated the effects of cannabidiol on AGSz behaviors in the primed DBA/1 mouse model of SUDEP.


Methods: The effects of cannabidiol on AGSz behaviors were examined in male and female DBA/1 mice that had undergone priming at 21-30 days of age. The mice were initially tested for susceptibility to AGSz behaviors- wild running, clonus, tonus, and seizure-induced respiratory arrest (S-IRA) after 3-4 daily seizures (priming). Seizures were initiated by presentation of an electrical bell at 122 dB SPL for 60 sec or until AGSz were induced. After priming all mice exhibited the full spectrum of seizure behaviors. Mice that exhibited S-IRA were resuscitated using a rodent respirator. At least 24 h after the final priming seizure the mice that exhibited all AGSz behaviors were given cannabidiol or vehicle by the intraperitoneal (i.p.) route and seizure behaviors were evaluated. The return to susceptibility to all AGSz behaviors following cannabidiol treatment was evaluated at 24-48 h. All seizures were video recorded, and changes in seizure behaviors were quantified and statistically compared offline (chi square test).


Results: Cannabidiol (50-200 mg/kg) in vehicle (1:1:18 Cremaphor:ethanol:0.9% saline) was administered to primed DBA/1 mice. At 100 mg cannabidiol significantly reduced AGSz behaviors at one or two hours after drug administration in both male and female mice. These effects were significant at p < 0.05. At 200 mg/kg cannabidiol exerted a greater degree of effect. However, the 50 mg/kg dose did not significantly reduce any AGSz behavior. Cannabidiol effects were tested 2 hours after administration in separate groups of DBA/1 mice at which time the anticonvulsant effects had slightly declined. The anticonvulsant effect was seen in both male and female mice with a slight but non-significant greater sensitivity of male mice at 200 mg/kg. The return to susceptibility to all AGSs behaviors following cannabidiol treatment occurred by 24-48 hours. The vehicle exerted no changes in any AGSz behaviors.