Disease‐Modifying Effects of RHC80267 and JZL184 in a Pilocarpine Mouse Model of Temporal Lobe Epilepsy

Summary Introduction Patients with temporal lobe epilepsy (TLE) often suffer from comorbid psychiatric diagnoses such as depression, anxiety, or impaired cognitive performance. Endocannabinoid (eCB) signaling is a key regulator of synaptic neurotransmission and has been implicated in the mechanisms of epilepsy as well as several mood disorders and cognitive impairments. Aims We employed a pilocarpine model of TLE in C57/BJ mice to investigate the role of eCB signaling in epileptogenesis and concomitant psychiatric comorbidities. Methods and Results We sought to alter the neuronal levels of a known eCB receptor ligand, 2‐arachidonylglycerol (2‐AG), through the use of RHC80267 or JZL184. Pilocarpine‐treated mice were treated with RHC80267 (1.3 μmol) or JZL184 (20 mg/kg) immediately after the termination of status epilepticus (SE), which was followed by daily treatment for the next 7 days. Our results indicated that RHC80267 treatment significantly reduced the percentage of mice suffering from spontaneous recurrent seizures (SRS) in addition to decreasing the duration of observed seizures when compared to vehicle treatment. Furthermore, RHC80267 attenuated depression and anxiety‐related behaviors, improved previously impaired spatial learning and memory, and inhibited seizure‐induced hippocampal neuronal loss during the chronic epileptic period. In contrast, JZL184 administration markedly increased the frequency and the duration of observed SRS, enhanced the previously impaired neuropsychological performance, and increased hippocampal damage following SE. Conclusions These findings suggest that RHC80267 treatment after the onset of SE could result in an amelioration of the effects found during the chronic epileptic period and yield an overall decrease in epileptic symptoms and comorbid conditions. Thus, alterations to endocannabinoid signaling may serve as a potential mechanism to prevent epileptogenesis and manipulation of this signaling pathway as a possible drug target.