Reduced cannabinoid 2 receptor activity increases susceptibility to induced seizures in mice

Abstract

Objective: The endocannabinoid system (ECS) is comprised of cannabinoid receptors 1 and 2 (CB1R and CB2R), endogenous ligands, and regulatory enzymes, and serves to regulate several important physiological functions throughout the brain and body. Recent evidence suggests that the ECS may be a promising target for the treatment of epilepsy, including epilepsy subtypes that arise from mutations in the voltage-gated sodium channel SCN1A. The objective of this study was to explore the effects of modulating CB2R activity on seizure susceptibility. Methods: We examined susceptibility to induced seizures using a number of paradigms in CB2R knockout mice (Cnr2 −/− ), and determined the effects of the CB2R agonist, JWH-133, and the CB2R antagonist, SR144528, on seizure susceptibility in wild-type mice. We also examined seizure susceptibility in Cnr2 mutants harboring the human SCN1A R1648H (RH) epilepsy mutation and performed Electroencephalography (EEG) analysis to determine whether the loss of CB2Rs would increase spontaneous seizure frequency in Scn1a RH mutant mice. Results: Both heterozygous (Cnr2 +/− ) and homozygous (Cnr2 −/− ) knockout mice exhibited increased susceptibility to pentylenetetrazole (PTZ)-induced seizures. The CB2R agonist JWH-133 did not significantly alter seizure susceptibility in wildtype mice; however, administration of the CB2R antagonist SR144528 resulted in increased susceptibility to PTZ-induced seizures. In offspring from a cross between the Cnr2 × RH lines, both Cnr2 and RH mutants were susceptible to PTZ-induced seizures; however, seizure susceptibility was not significantly increased in mutants expressing both mutations. No spontaneous seizures were observed in either RH or Cnr2/RH mutants during 336-504 hours of continuous EEG recordings. Significance: Our results demonstrate that reduced CB2R activity is associated with increased seizure susceptibility. CB2Rs might therefore provide a therapeutic target for the treatment of some forms of epilepsy. K E Y W O R D Scannabinoid 2 receptor, CB2R agonist, CB2R antagonist, SCN1A, seizure susceptibility 2360 | SHAPIRO et Al.

Neural Stem Cells and Cannabinoids in the Spotlight as Potential Therapy for Epilepsy

“…Likewise, in the pilocarpine rat model, CB2R expression was upregulated in the hippocampus following SE [ 204 ]. Taken together, both these studies suggest a putative neuroprotective action of eCBs via CB2R in epilepsy [ 203 , 204 ].…”

“…More recently, CB2R has also been shown to be systemically activated to modulate immune-mediated symptoms associated with seizure-induced-neuroinflammation [ 199 , 200 ] (reviewed in References [ 201 , 202 ]). Interestingly, CB2R knockout mice exhibited an increased susceptibility to induced seizures [ 203 ]. Likewise, in the pilocarpine rat model, CB2R expression was upregulated in the hippocampus following SE [ 204 ].…”

“…In pathological conditions, where neurogenesis has been found to be disrupted, such as epilepsy, Alzheimer’s, or Parkinson’s Diseases, disturbances associated with ECS homeostasis were also found [ 203 , 237 , 238 , 239 , 240 , 241 ] (reviewed in References [ 113 , 242 , 243 , 244 ]). Thus, it may be proposed that an interplay between the rise of symptomatology of these disorders may be originated from a combined early impairment in neural development or aberrant adult neurogenesis with deficiencies in the ECS.…”

Cannabinoid Receptors: An Update on Cell Signaling, Pathophysiological Roles and Therapeutic Opportunities in Neurological, Cardiovascular, and Inflammatory Diseases

“…Apart from ambiguity over the CB1R’s role in the prevention of epileptic seizures, and the potential to induce psychological adverse effects, there is also some concern over the effectiveness of targeting CB1R solely as a therapeutic strategy [ 360 , 361 ]. By employing animal and cell culture models of epilepsy, several studies have demonstrated that CB2R is involved in conferring a protective phenotype to a variety of seizure types [ 362 , 363 , 364 ]. CB2R, which is primarily expressed on activated microglial cells, induced astroglial cell proliferation and survival in an astrocyte model of epilepsy [ 363 ].…”

Mice Lacking Connective Tissue Growth Factor in the Forebrain Exhibit Delayed Seizure Response, Reduced C-Fos Expression and Different Microglial Phenotype Following Acute PTZ Injection

“…In this study, we adopted an acute pentylenetetrazole (PTZ) paradigm to induce seizures in control and Fb Ctgf KO mice. PTZ is a bicyclic tetrazol derivative that suppresses GABAergic neurotransmission and has long been used for inducing convulsions and seizures in various animal models [ 26 , 27 , 28 , 29 , 30 ]. We scored PTZ-induced seizure behaviors and measured c-fos expression as well as glial responses in the mouse brain.…”