Protective Effects of Cannabidiol against Seizures and Neuronal Death in a Rat Model of Mesial Temporal Lobe Epilepsy

Abstract

The present study reports the behavioral, electrophysiological, and neuropathological effects of cannabidiol (CBD), a major non-psychotropic constituent of Cannabis sativa, in the intrahippocampal pilocarpine-induced status epilepticus (SE) rat model. CBD was administered before pilocarpine-induced SE (group SE+CBDp) or before and after SE (group SE+CBDt), and compared to rats submitted only to SE (SE group), CBD, or vehicle (VH group). Groups were evaluated during SE (behavioral and electrophysiological analysis), as well as at days one and three post-SE (exploratory activity, electrophysiological analysis, neuron density, and neuron degeneration). Compared to SE group, SE+CBD groups (SE+CBDp and SE+CBDt) had increased SE latency, diminished SE severity, increased contralateral afterdischarge latency and decreased relative powers in delta (0.5–4 Hz) and theta (4–10 Hz) bands. Only SE+CBDp had increased vertical exploratory activity 1-day post SE and decreased contralateral relative power in delta 3 days after SE, when compared to SE group. SE+CBD groups also showed decreased neurodegeneration in the hilus and CA3, and higher neuron density in granule cell layer, hilus, CA3, and CA1, when compared to SE group. Our findings demonstrate anticonvulsant and neuroprotective effects of CBD preventive treatment in the intrahippocampal pilocarpine epilepsy model, either as single or multiple administrations, reinforcing the potential role of CBD in the treatment of epileptic disorders.

Cannabidiol reduces seizures and associated behavioral comorbidities in a range of animal seizure and epilepsy models

“…More than 100 phytocannabinoids have been isolated, of which Δ 9 ‐tetrahydrocannabinol, cannabidiol (CBD), and cannabidivarin are considered most relevant in the treatment of epilepsy; however, Δ 9 ‐tetrahydrocannabinol has poor clinical potential due to its psychoactive and potential proconvulsive properties, which may limit chronic use . CBD has been shown to have antiseizure activity in several animal models . Given its anticonvulsant efficacy in phase 3 clinical trials, the US Food and Drug Administration (FDA) in 2018 approved CBD (Epidiolex; GW Research) as a drug for the treatment of seizures associated with Dravet syndrome or Lennox‐Gastaut syndrome in patients 2 years of age and older …”

“…The pilocarpine‐induced SE model is typically sensitive to most ASDs when they are administered prior to or commensurate with SE onset; nonetheless, this model is useful to interrogate pharmacological efficacy in a severe seizure model. Finally, there is little information on the potential of CBD to modify epilepsy‐related behavioral comorbidities despite its preclinical and clinical ability to provide acute seizure control . Furthermore, no preclinical study has yet shown that sustained exposure to CBD not only reduces seizure burden in a temporal lobe epilepsy (TLE) model but can also attenuate the severity of the associated behavioral comorbidities.…”

“…1,6 CBD has been shown to have antiseizure activity in several animal models. 6,[8][9][10] Given its anticonvulsant efficacy in phase 3 clinical trials, the US Food and Drug Administration (FDA) in 2018 approved CBD (Epidiolex; GW Research) as a drug for the treatment of seizures associated with Dravet syndrome or Lennox-Gastaut syndrome in patients 2 years of age and older. [11][12][13] Here, we initially tested CBD in a battery of well-established preclinical seizure and epilepsy models following intraperitoneal administration to define CBD's pharmacological profile and differentiate it from other ASD standards of care.…”

Is cannabidiol a drug acting on unconventional targets to control drug‐resistant epilepsy?

“…Several studies support that CBD could be effective in the control of epilepsy . Results obtained from experimental models reveal that CBD reduces the seizure activity and delays the epileptogenesis process, effects associated with neuroprotection . CBD in oral solution (Epidiolex ® ) is considered a therapy to control seizures associated with the Lennox‐Gastaut syndrome, Dravet syndrome, and infantile spasms .…”

“…57 CBD induces neuroprotection, decreased neuronal excitability, and avoids cell death in the hippocampus of animals with temporal lobe epilepsy. 50,58 However, the effects of CBD in other types of drug-resistant epilepsy are not conclusive due to the presence of subjects who do not respond to the treatment. [59][60][61][62] Clinical data in humans indicate that CBD-rich extracts are more effective to reduce the seizure frequency when compared with purified CBD.…”