Cannabidiol reduces seizures and associated behavioral comorbidities in a range of animal seizure and epilepsy models

Abstract

Summary Objective Epilepsy is a progressive neurological disease characterized by recurrent seizures and behavioral comorbidities. We investigated the antiseizure effect of cannabidiol ( CBD ) in a battery of acute seizure models. Additionally, we defined the disease‐modifying potential of chronic oral administration of CBD on associated comorbidities in the reduced intensity status epilepticus–spontaneous recurrent seizures ( RISE ‐ SRS ) model of temporal lobe epilepsy ( TLE ). Methods We evaluated the acute antiseizure effect of CBD in the maximal electroshock seizure, 6‐Hz psychomotor seizure, and pentylenetetrazol acute seizure tests, as well as the corneal kindling model of chronic seizures in mice following intraperitoneal administration. Median effective or behavioral toxic dose was determined in both mice and rats. Next, we tested an intravenous preparation of CBD (10 mg/kg single dose) in a rat model of pilocarpine‐induced status epilepticus. We defined the effect of chronic CBD administration (200 mg/kg orally) on spontaneous seizures, motor control, gait, and memory function in the rat RISE ‐ SRS model of TLE . Results CBD was effective in a battery of acute seizure models in both mice and rats following intraperitoneal administration. In the pilocarpine‐induced status epilepticus rat model, CBD attenuated maximum seizure severity following intravenous administration, further demonstrating CBD 's acute antiseizure efficacy in this rat model. We established that oral CBD attenuated the time‐dependent increase in seizure burden and improved TLE ‐associated motor comorbidities of epileptic rats in the RISE ‐ SRS model without affecting gait. Chronic administration of CBD after the onset of SRS ameliorated reference memory and working memory errors of epileptic animals in a spatial learning and memory task. Significance The present study illustrates that CBD is a well‐tolerated and effective antiseizure agent and illustrates a potential disease‐modifying effect of CBD on reducing both seizure burden and associated comorbidities well after the onset of symptomatic seizures in a model of TLE .

Cannabidiol improves survival and behavioural co‐morbidities of Dravet syndrome in mice

“…We showed that CBD improved both the reference and WM function of Scn1a +/− mice compared to their vehicle‐treated counterparts, to our knowledge, the first report of improving cognitive deficiencies in a model of Dravet syndrome. We have previously reported a similar reversal of cognitive deficits in a rat model of temporal lobe epilepsy (Patra et al, ), which may suggest that CBD has a more generalised role in protecting cognitive function in epilepsy, perhaps related to reduction in seizure frequency or severity. Further to this spatial learning memory deficits in a mouse model of Alzheimer's disease were attenuated by CBD in a CB 2 receptor‐independent manner (Martin‐Moreno et al, ).…”

“…Cannabidiol (CBD) is one of the most abundant plant‐derived cannabinoids. It is non‐euphoric and has shown potential for use in treating seizures, epilepsy, epileptogenesis and related neuroprotection in a number of animal models including Dravet syndrome (Kaplan, Stella, Catterall, & Westenbroek, ; Patra et al, ; Rosenberg, Patra, & Whalley, ). CBD was demonstrated to be an effective anticonvulsant in Phase 3 clinical trials for the treatment of Dravet syndrome and Lennox Gastaut Syndrome and in 2018 received FDA approval in the United States for seizures associated with these disorders (Devinsky et al, ; FDA, ; Thiele et al, ).…”

Is cannabidiol a drug acting on unconventional targets to control drug‐resistant epilepsy?

“…Several studies support that CBD could be effective in the control of epilepsy . Results obtained from experimental models reveal that CBD reduces the seizure activity and delays the epileptogenesis process, effects associated with neuroprotection . CBD in oral solution (Epidiolex ® ) is considered a therapy to control seizures associated with the Lennox‐Gastaut syndrome, Dravet syndrome, and infantile spasms .…”

The Endocannabinoid System Activation as a Neural Network Desynchronizing Mediator for Seizure Suppression

“…Cannabis's primary active substance is delta-9-tetrahydrocannabinol (THC; Mechoulam, 1970). However, various other compounds are interesting from a pharmacological standpoint, including cannabidiol (CBD), delta-9-tetrahydrocannabivarin, cannabidivarin, among others (Hill et al, 2013;Patra et al, 2019).…”