Antiseizure properties of cannabidiol (CBD) are attenuated in the absence of transient receptor potential vanilloid 1 (TRPV1) receptors (S53.004)

Objective: Evaluate effect of CBD upon seizure threshold in wild-type (WT) and TRPV1 knockout (TRPV1−/−) mice.

Background: TRPV1 receptor expression is increased in rodent epilepsy models and temporal lobe epilepsy patients. CBD is a TRPV1 agonist that rapidly desensitizes TRPV1. A pharmaceutical formulation of purified CBD has been shown to reduce seizure frequency in Lennox-Gastaut and Dravet syndrome patients.

Design/Methods: Mice received intraperitoneal CBD (10–200 mg/kg; GW Pharmaceuticals), CBD vehicle (ethanol:kolliphorEL:saline, 1:1:18 ratio) 60 minutes before testing, the TRPV1 antagonist capsazepine (10 mg/kg in 2% DMSO), or diazepam (2.5 mg/kg in saline) 30 minutes before testing (n=12/group). A constant current stimulus (1–300 mA; 0.1 s duration) was delivered via corneal electrodes and mice assessed for tonic hind limb extension. Stimulus intensity was varied by a shock titration method and the current required to produce maximal seizures in 50% of animals tested (CC₅₀) values calculated. Statistical analysis was performed using two-way ANOVA with post-hoc Sidak’s tests. Brain and plasma CBD concentrations were assessed by liquid chromatography/tandem mass spectrometry.

Results: There was a significant interaction between genotype and disease (F_(6,154)=24.35; P<0.0001) and main effects of genotype (F_(1,154)=169.6; P<0.0001) and treatment (F_(6,154)=113.4; P<0.001) upon CC₅₀ which arose from significantly attenuated responses in TRPV1−/− mice to CBD (50 & 100 mg/kg; each P<0.0001), diazepam (P<0.001) and capsazepine (P<0.05) when compared to WT. No significant difference in brain CBD concentrations was noted between WT and TRPV1−/− mice (P>0.05).

Conclusions: CBD dose-dependently increased seizure threshold in WT mice, an effect markedly reduced in TRPV1−/− mice. Brain CBD concentrations were consistent with those required for TRPV1 activation and desensitization, suggesting that CBD’s anticonvulsant effects in acute, generalized seizures are partially mediated via TRPV1 receptor interaction.

Study Supported by:

GW Research Ltd

Disclosure: Dr. Whalley has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with GW PHARMACEUTIALS (EMPLOYMENT). Dr. Whalley holds stock and/or stock options in GW PHARMACEUTICALS, which sponsored research in which Dr. Whalley was involved as an investigator. Dr. Gray has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with GW Pharmaceuticals. Dr. Gray has received compensation for serving on the Board of Directors of GW Pharmaceuticals. Dr. Stott has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with GW Pharmaceuticals. Dr. Stott has received compensation for serving on the Board of Directors of GW Pharmaceuticals. Dr. Stott holds stock and/or stock options in GW Pharmaceuticals, which sponsored research in which Dr. Stott was involved as an investigator. Dr. Jones has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with GW Pharmaceuticals. Dr. Jones has received compensation for serving on the Board of Directors of GW Pharmaceuticals.