PopulationRatten im Pilocarpin-Epilepsie-Modell (spontane, rezidivierende Anfälle), Tiermodell
I
InterventionΔ9-THC (10 mg/kg i.p.) und CB1-Agonist R(+)WIN55,212 (5 mg/kg); alternativ CB1-Antagonist SR141716A
C
KontrolleKontrolltiere ohne Behandlung bzw. Vergleich zwischen Agonist- und Antagonist-Bedingungen
O
OutcomeTHC und WIN55,212 eliminierten spontane epileptische Anfälle vollständig; SR141716A erhöhte Anfallsdauer und -frequenz signifikant, teils bis Status epilepticus; 2-AG-Spiegel im Hippocampus stiegen während akuter Anfälle signifikant an; CB1-Protein-Expression in CA-Regionen epileptischer Hippocampi signifikant erhöht
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Autoren
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.