The CB₂ receptor as a novel therapeutic target for epilepsy treatment

Epilepsy is characterized by repeated spontaneous bursts of neuronal hyperactivity and high synchronization in the central nervous system. It seriously affects the quality of life of epileptic patients, and nearly 30% of individuals are refractory to treatment of antiseizure drugs. Therefore, there is an urgent need to develop new drugs to manage and control refractory epilepsy. Cannabinoid ligands, including selective cannabinoid receptor subtype (CB₁ or CB₂ receptor) ligands and non-selective cannabinoid (synthetic and endogenous) ligands, may serve as novel candidates for this need. Cannabinoid appears to regulate seizure activity in the brain through the activation of CB₁ and CB₂ cannabinoid receptors (CB₁R and CB₂R). An abundant series of cannabinoid analogues have been tested in various animal models, including the rat pilocarpine model of acquired epilepsy, a pentylenetetrazol model of myoclonic seizures in mice, and a penicillin-induced model of epileptiform activity in the rats. The accumulating lines of evidence show that cannabinoid ligands exhibit significant benefits to control seizure activity in different epileptic models. In this review, we summarize the relationship between brain CB₂ receptors and seizures and emphasize the potential mechanisms of their therapeutic effects involving the influences of neurons, astrocytes, and microglia cells. The unique features of CB₂Rs, such as lower expression levels under physiological conditions and high inducibility under epileptic conditions, make it an important target for future research on drug-resistant epilepsy.