2-Linoleoylglycerol decreased seizure through the regulation of 5-hydroxytryptamine 1A receptor and G protein-coupled receptor 55 interaction in mice.

BACKGROUND: Epilepsy is a central nervous system disorder characterized by abnormal brain activity, leading to seizures or periods of unusual behavior, sensations, and, in some cases, loss of awareness. Cannabidiol, a phytocannabinoid, has recently gained approval as an adjunctive seizure treatment, partly through modulation of G protein-coupled receptor 55 (GPR55), transient receptor potential vanilloid 1, and 5-hydroxytryptamine (5-HT) receptors. Similar to phytocannabinoids, endocannabinoids may also possess therapeutic potential for seizure management; however, no studies have investigated the effects of the endocannabinoid 2-linoleoylglycerol (2-LG). In the present study, we investigated the effects of 2-LG on pentylenetetrazol (PTZ)-induced seizures in mice.

METHODS: Mice were pretreated with 0 (vehicle), 15, or 30 mg/kg 2-LG intraperitoneally, and saline or 60 mg/kg PTZ was administered 30 min later. Vehicle, WAY-100635 (0.01 mg/kg), or rimonabant (1 mg/kg) were administered 30 min before 2-LG (30 mg/kg) administration, and then saline or 60 mg/kg PTZ was administered 30 min later.

RESULTS: Administration of 2-LG (30 mg/kg) significantly reduced seizure scores induced by PTZ. In addition, pretreatment with the 5-HT1A receptor antagonist WAY-100635 reversed the 2-LG antiseizure effect. We also demonstrated that PTZ-induced fluorescence intensity of the GPR55 ligand T1117 in the hippocampus was decreased by 2-LG treatment, and this effect was reversed by WAY-100635 pretreatment. Similarly, the cannabinoid receptor type 1 inverse agonist rimonabant inhibited the antiseizure activity of 2-LG, although it did not significantly affect T1117 fluorescence.

CONCLUSION: These results suggest that 2-LG exerts an antiseizure effect through interactions between the 5-HT1A receptor and GPR55.