Pharmacological characterization of the cannabinoid receptor 2 agonist, β-caryophyllene on seizure models in mice

Seizure. 2018 Apr;57:22-26. doi: 10.1016/j.seizure.2018.03.009. Epub 2018 Mar 12.


Purpose: Activation of CB1 receptors, produces anticonvulsant effect accompanied by memory disturbance both in animal seizure tests and in patients with epilepsy. Few reports considered the role of CB2 receptor on seizure susceptibility and cognitive functions. The aim of the present study was to explore the effect of a selective CB2 receptor agonist β-caryophyllene (BCP) in models of seizures and cognition in mice.

Methods: Dose-dependent effects of BCP was studied in maximal electroshock seizure (MES) test, subcutaneous pentylenetetrazole (scPTZ) test and Morris water maze test. Phenytoin and diazepam were used as reference drugs in seizure tests. The effect of sub-chronic treatment with BCP for 7 days (50 and 100 mg kg-1) was assessed on status epilepticus (SE) induced by kainic acid (KA) model and oxidative stress through measurement of malondialdehyde (MDA) level in the hippocampus. The acute neurotoxicity was determined by a rotarod test.

Results: The BCP exerted a protection in the MES test at the lowest dose of 30 mg kg-1 at the 4-h interval tested comparable to that of the referent drug phenytoin. The CB2 agonist was ineffective in the scPTZ test. The BCP displayed no neurotoxicity in the rotarod test. The BCP decreased the seizure scores in the KA-induced SE, which effect correlated with a diminished lipid peroxidation. The CB2 agonist exerted a dose-dependent decrease of latency to cross the target area during the three days of testing in the Morris water maze test.

Conclusion: Our results suggest that the CB2 receptor agonists might be clinically useful as an adjunct treatment against seizure spread and status epilepticus and concomitant oxidative stress, neurotoxicity and cognitive impairments.

Keywords: CB2 receptor agonist; Kainic acid; MES test; Mice; Oxidative stress; scPTZ test.

MeSH terms

  • Animals
  • Anticonvulsants / pharmacology*
  • Cannabinoid Receptor Agonists / pharmacology*
  • Diazepam / pharmacology
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Electroshock
  • Hippocampus / drug effects
  • Hippocampus / metabolism
  • Kainic Acid
  • Male
  • Malondialdehyde / metabolism
  • Maze Learning / drug effects
  • Mice, Inbred ICR
  • Motor Activity / drug effects
  • Pentylenetetrazole
  • Phenytoin / pharmacology
  • Polycyclic Sesquiterpenes
  • Receptor, Cannabinoid, CB2 / agonists*
  • Receptor, Cannabinoid, CB2 / metabolism
  • Seizures / drug therapy*
  • Seizures / metabolism
  • Sesquiterpenes / pharmacology*
  • Status Epilepticus / drug therapy
  • Status Epilepticus / metabolism


  • Anticonvulsants
  • Cannabinoid Receptor Agonists
  • Cnr2 protein, mouse
  • Polycyclic Sesquiterpenes
  • Receptor, Cannabinoid, CB2
  • Sesquiterpenes
  • Malondialdehyde
  • Phenytoin
  • caryophyllene
  • Diazepam
  • Kainic Acid
  • Pentylenetetrazole