Inverse Agonism of Cannabinoid Receptor Type 2 Confers Anti-inflammatory and Neuroprotective Effects Following Status Epileptics.

Prolonged status epilepticus (SE) in humans causes high mortality and brain inflammation-associated neuronal injury and morbidity in survivors. Currently, the only effective treatment is to terminate the seizures swiftly to prevent brain damage. However, reliance on acute therapies alone would be imprudent due to the required short response time. Follow-on therapies that can be delivered well after the SE onset are in an urgent need. Cannabinoid receptor type 2 (CB2), a G protein-coupled receptor that can be expressed by activated brain microglia, has emerged as an appealing anti-inflammatory target for brain conditions. In the current study, we reported that the CB2 inverse agonism by our current lead compound SMM-189 largely prevented the rat primary microglia-mediated inflammation and showed moderate neuroprotection against N-methyl-D-aspartic acid (NMDA) receptor-mediated excitotoxicity in rat primary hippocampal cultures containing both neurons and glia. Using a classical mouse model of epilepsy, in which SE was induced by systemic administration of kainate (30 mg/kg, i.p.) and proceeded for 1 h, we demonstrated that SE downregulated the CB1 but slightly upregulated CB2 receptor in the hippocampus. Transient treatment with SMM-189 (6 mg/kg, i.p., b.i.d.) after the SE was interrupted by diazepam (10 mg/kg, i.p.) prevented the seizure-induced cytokine surge in the brain, neuronal death, and behavioral impairments 24 h after SE. Our results suggest that CB2 inverse agonism might provide an adjunctive anti-inflammatory therapy that can be delivered hours after SE onset, together with NMDA receptor blockers and first-line anti-convulsants, to reduce brain injury and functional deficits following prolonged seizures.

G protein-coupled receptors in acquired epilepsy: Druggability and translatability.

As the largest family of membrane proteins in the human genome, G protein-coupled receptors (GPCRs) constitute the targets of more than one-third of all modern medicinal drugs. In the central nervous system (CNS), widely distributed GPCRs in neuronal and nonneuronal cells mediate numerous essential physiological functions via regulating neurotransmission at the synapses. Whereas their abnormalities in expression and activity are involved in various neuropathological processes. CNS conditions thus remain highly represented among the indications of GPCR-targeted agents. Mounting evidence from a large number of animal studies suggests that GPCRs play important roles in the regulation of neuronal excitability associated with epilepsy, a common CNS disease afflicting approximately 1-2% of the population. Surprisingly, none of the US Food and Drug Administration (FDA)-approved (>30) antiepileptic drugs (AEDs) suppresses seizures through acting on GPCRs. This disparity raises concerns about the translatability of these preclinical findings and the druggability of GPCRs for seizure disorders. The currently available AEDs intervene seizures predominantly through targeting ion channels and have considerable limitations, as they often cause unbearable adverse effects, fail to control seizures in over 30% of patients, and merely provide symptomatic relief. Thus, identifying novel molecular targets for epilepsy is highly desired. Herein, we focus on recent progresses in understanding the comprehensive roles of several GPCR families in seizure generation and development of acquired epilepsy. We also dissect current hurdles hindering translational efforts in developing GPCRs as antiepileptic and/or antiepileptogenic targets and discuss the counteracting strategies that might lead to a potential cure for this debilitating CNS condition.