CB1 activation by THC or synthetic cannabinoids eliminated spontaneous seizures, while CB1 blockade enhanced seizure activity.
Summary
Rat model of spontaneous recurrent seizures (pilocarpine): Δ9-THC (10 mg/kg) and CB1 agonist WIN55,212 (5 mg/kg) completely suppressed epileptic seizures; CB1 antagonist SR141716A significantly increased seizure duration and frequency (in some cases equivalent to status epilepticus). Hippocampal 2-arachidonylglycerol levels increased significantly during acute seizures; CB1 receptor protein in CA regions of epileptic hippocampi significantly increased.
P
PopulationRats in the pilocarpine epilepsy model (spontaneous, recurrent seizures), animal model
ControlUntreated control animals or comparison between agonist and antagonist conditions
O
OutcomeTHC and WIN55,212 completely eliminated spontaneous epileptic seizures; SR141716A significantly increased seizure duration and frequency, in some cases up to status epilepticus; 2-AG levels in the hippocampus increased significantly during acute seizures; CB1 protein expression in CA regions of epileptic hippocampi significantly increased
Confidence in the evidence
Very lowLowModerateHigh
Very low
The lowest GRADE level, the effect estimate remains uncertain.
Quality profile
Sample size—
Blinding—
Effect sizeClear benefit
Citations / year★★★★★
Authors
Wallace MJ, Blair RE, Falenski KW, Martin BR, DeLorenzo RJ.
Several lines of evidence suggest that cannabinoid compounds are anticonvulsant. However, the anticonvulsant potential of cannabinoids and, moreover, the role of the endogenous cannabinoid system in regulating seizure activity has not been tested in an in vivo model of epilepsy that is characterized by spontaneous, recurrent seizures. Here, using the rat pilocarpine model of epilepsy, we show that the Cannabis extract Delta9-tetrahydrocannabinol (10 mg/kg) as well as the cannabimimetic, 4,5-dihydro-2-methyl-4(4-morpholinylmethyl)-1-(1-naphthalenyl-carbonyl)-6H-pyrrolo[3,2,1-i,j]quinolin-6-one [R(+)WIN55,212 (5 mg/kg)], completely abolished spontaneous epileptic seizures. Conversely, application of the cannabinoid CB1 receptor (CB1) antagonist, N-(piperidin-1-yl-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamidehydrochloride (SR141716A), significantly increased both seizure duration and frequency. In some animals, CB1 receptor antagonism resulted in seizure durations that were protracted to a level consistent with the clinical condition status epilepticus. Furthermore, we determined that during an short-term pilocarpine-induced seizure, levels of the endogenous CB1 ligand 2-arachidonylglycerol increased significantly within the hippocampal brain region. These data indicate not only anticonvulsant activity of exogenously applied cannabinoids but also suggest that endogenous cannabinoid tone modulates seizure termination and duration through activation of the CB1 receptor. Furthermore, Western blot and immunohistochemical analyses revealed that CB1 receptor protein expression was significantly increased throughout the CA regions of epileptic hippocampi. By demonstrating a role for the endogenous cannabinoid system in regulating seizure activity, these studies define a role for the endogenous cannabinoid system in modulating neuroexcitation and suggest that plasticity of the CB1 receptor occurs with epilepsy.