Cannabidiol Displays Antiepileptiform and Antiseizure Properties In Vitro and In Vivo

Abstract

Plant-derived cannabinoids (phytocannabinoids) are compounds with emerging therapeutic potential. Early studies suggested that cannabidiol (CBD) has anticonvulsant properties in animal models and reduced seizure frequency in limited human trials. Here, we examine the antiepileptiform and antiseizure potential of CBD using in vitro electrophysiology and an in vivo animal seizure model, respectively. CBD (0.01-100 M) effects were assessed in vitro using the Mg 2ϩ -free and 4-aminopyridine (4-AP) models of epileptiform activity in hippocampal brain slices via multielectrode array recordings. In the Mg 2ϩ -free model, CBD decreased epileptiform local field potential (LFP) burst amplitude [in CA1 and dentate gyrus (DG) regions] and burst duration (in all regions) and increased burst frequency (in all regions). In the 4-AP model, CBD decreased LFP burst amplitude (in CA1, only at 100 M CBD), burst duration (in CA3 and DG), and burst frequency (in all regions). CBD (1, 10, and 100 mg/kg) effects were also examined in vivo using the pentylenetetrazole model of generalized seizures. CBD (100 mg/ kg) exerted clear anticonvulsant effects with significant decreases in incidence of severe seizures and mortality compared with vehicle-treated animals. Finally, CBD acted with only low affinity at cannabinoid CB 1 receptors and displayed no agonist activity in [35 S]guanosine 5Ј-O-(3-thio)-triphosphate assays in cortical membranes. These findings suggest that CBD acts, potentially in a CB 1 receptor-independent manner, to inhibit epileptiform activity in vitro and seizure severity in vivo. Thus, we demonstrate the potential of CBD as a novel antiepileptic drug in the unmet clinical need associated with generalized seizures.

Cannabidiol exerts antiepileptic effects by restoring hippocampal interneuron functions in a temporal lobe epilepsy model

“…Substances were injected i.p. The dose of CBD injected into rats was approximately the ED 50 for animal seizure models in the National Institute of Neurological Disorders and Stroke screening (Jones et al, 2010). …”

“…http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2424, Δ 9 ‐THC) that act through cannabinoid type‐1 (http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=56) receptors (Consroe and Wolkin, 1977; Consroe et al, 1982; Kogan and Mechoulam, 2007; Jones et al, 2010; 2012), making the cannabinoid system an interesting and novel therapeutic target for epilepsy. These observations have been corroborated by recent human clinical studies, where CBD reduced the convulsive seizure frequency by 50%, giving hope for patient groups with uncontrollable epilepsy where other drug treatments have failed, namely, in a complex childhood epilepsy disorder associated with high mortality rate, Dravet syndrome (Devinsky et al, 2017).…”

Cannabinoids and Epilepsy

“…CBD has very low affinity at CB 1 R and CB 2 R, unlike Δ9-THC [103][104][105][106]. The potential targets for CBD are reviewed in detail in another article in this issue ("Molecular Targets of CBD in Neurological Disorders").…”

Cannabidiol inhibits synaptic transmission in rat hippocampal cultures and slices via multiple receptor pathways

“…Despite increasing evidence to suggest that CBD has multiple targets (Pertwee, 2008;Izzo et al, 2009), the effect of CBD on basal synaptic transmission has yet to be determined although a recent study has demonstrated clear anti-epileptiform and antiseizure activity (Jones et al, 2010). In the present study, we have examined the effect of CBD upon synaptic activity in primary hippocampal cultures and acute hippocampal slices.…”