Anticonvulsant Effects of Cannabidiol in Mouse Models of Epilepsy
Abstract number :
1.284
Submission category :
7. Antiepileptic Drugs / 7A. Animal Studies
Year :
2018
Submission ID :
501922
Source :
www.aesnet.org
Presentation date :
12/1/2018 6:00:00 PM
Published date :
Nov 5, 2018, 18:00 PM
Authors :
Paulo Rodrigues, University of Wisconsin; Jesse Pfammatter, University of Wisconsin; Sai Sruthi Konduru, University of Wisconsin; Claudia Aldrich, University of Wisconsin; Eli Wallace, University of Wisconsin; Mathew Jones, University of Wisconsin; and Ra
Rationale: One-third of patients with epilepsy remain intractable to currently available treatments. In the recent past there had been interest in antiepileptic effects of Cannabinoids, like ?9-tetrahydrocannabinol (THC), cannabidivarin and cannabidiol (CBD). Of these, CBD is shown exert anticonvulsant effects in certain epilepsy syndromes1-2, but the exact mechanism of action is not known. Some reports pointed to effects on mTOR signaling3, an important biochemical signaling pathway implicated in developmental brain malformations, autism and epilepsy. The goal of this study was to study the anticonvulsant effects of CBD in induced and genetic models of epilepsy and reveal the mechanisms of anticonvulsant effects of CBD, focusing on the mTOR signaling pathway. Methods: We used a genetic model of epilepsy, Kv1.1-/- mice and an induced model, repeated low dose kainate. EEG and EMG were implanted in these mice at p35, and following recovery from surgery, seizures and high amplitude, 50-200 ms events (i.e. inter-ictal spikes and sharp waves) were monitored during a 5-day period in which animals were given IP injections of CBD (n=7, dose: 100 mg/Kg) or a vehicle, DMSO (control, n=7) during days 2, 3, and 4 or recording. Results: 5/7 DMSO treated animals died during recording as compared to only 1/7 CBD treated animals (Death occurring about P40-42). Animals treated with CBD had significantly less frequency of high amplitude spikes and sharps compared to DMSO treated animals (P = 0.001). Additionally, animals treated with CBD had less total number of seizures that those treated with DMSO (P = 0.98). To determine whether CBD exerts its effects via the mTOR pathway, we are currently in progress of performing additional EEG recordings, as animals are treated with CBD alone, Torin2 alone (an mTOR blocker), CBD + Torin2, all given along with a vehicle (DMSO) or vehicle alone with each unique drug treatment given to WT and saline treated controls as well in both models. Conclusions: CBD appears to delay mortality but also reduce frequency of epileptiform spikes and sharp waves in epileptic Kv1.1-/- mice. CBD thus far is found to have modest effects on seizure frequency in the Kv1.1-/- model. Additionally, the study is expected to yield insights into the potential mechanism of action of CBD in 2 mouse models of epilepsy. Funding: Study was funded by a Pilot Grant from Epilepsy Foundation of America.