The Endogenous Cannabinoid System Regulates Seizure Frequency and Duration in a Model of Temporal Lobe Epilepsy

Abstract

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 marijuana extract ⌬ 9 -tetrahydrocannabinol (10 mg/kg) as well as the cannabimimetic, 4, significantly increased both seizure duration and frequency. In some animals, CB 1 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 CB 1 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 CB 1 receptor. Furthermore, Western blot and immunohistochemical analyses revealed that CB 1 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 CB 1 receptor occurs with epilepsy.

Cannabinoids and Epilepsy

“…CBDV potentiated the effects of phenobarbital, ethosuximide, and valproate in 2 seizure models [181]. These studies suggest that both Δ9-THC and CBD provide significant protection from seizures [147,[154][155][156][157][158][159][160][161][162][163][164][165][166]. GABA = γ-aminobutryic acid in preclinical animal trials, presenting potential targets for human studies.…”

“…Levels of CB 1 R expression in the CA1-3 stratum oriens and radiatum (presumed excitatory inputs) and dentate gyrus steadily increased 1-week post-pilocarpine-induced seizures (Fig. 3, dark green trace) [147,[155][156][157][158]. However, sclerotic and nonsclerotic hippocampal tissue resected from patients with epilepsy displayed a reduction in DAGLα (2-AG biosynthetic enzyme), CB 1 R mRNA, and CB 1 R excitatory terminal immunoreactivity (Fig.…”

“…Kainic acid (KA) (30 mg/kg)-induced seizures increased levels of the anandamide in wild-type mice (20 min postinjection) [146], and pilocarpine (375 mg/kg)-induced seizures increased levels of 2-AG (15 min postseizure onset) [147]. Thus, epileptiform activity triggers a neuroprotective, on-demand release of endocannabinoids (or increase endocannabinoid levels in a downstream pathway unrelated to neuroprotection).…”

Inhibition of endocannabinoid metabolism attenuates enhanced hippocampal neuronal activity induced by kainic acid

“…Previous in vitro and in vivo studies have shown that exogenously applied CB receptor agonists, such as D 9 THC and WIN 55, 212-2 are antiepileptic in a number of animal seizure models. This includes in vivo models of maximal electroshock in mice (Wallace et al, 2001) and the pilocarpine model in rats (Wallace et al, 2003), and in vitro, in hippocampal neuronal culture models of acquired epilepsy and status epilepticus (Blair et al, 2006). Moreover, endocannabinoids such as AEA and 2-AG have been shown to exhibit neuroprotective effects (Marsicano et al, 2003) and antiepileptic effects when applied exogenously (Wallace et al, 2002).…”

Long-term decrease in calbindin-D28K expression in the hippocampus of epileptic rats following pilocarpine-induced status epilepticus

“…Gel electrophoresis was carried out on rat hippocampal cytosolic fractions from control and epileptic animals as previously described (Wallace et al, 2003). Briefly, hippocampi were homogenized and crude membranes were removed by centrifugation (Morris et al, 2000).…”