Bench to bedside: Multiple facets of cannabinoid control in epilepsy

Epilepsy is a neurological disease recognized as the consequence of excessive neuronal excitability. Endocannabinoid system, the critical regulator of synaptic inhibition in brain, was supposed to be closely involved in epilepsy. Cannabinoid receptors mostly locate on presynaptic terminals of both excitatory and inhibitory neurons, but with characteristic distribution varying in different brain areas and synapses. Endocannabinoids are synthesized in postsynaptic neurons and retrogradely act on presynaptic cannabinoid receptors. Accumulating evidence suggest that the expression of cannabinoid receptors and synthesis or breakdown of endocannabinoids were cell-type specifically altered and spatiotemporally regulated in seizures, and intervention of the expression of cannabinoid receptors or the level of endocannabinoids could affect seizure actions. Further in clinic, cannabidiol as an add-on treatment could reduce seizures in patients with treatment-resistant epilepsy, but the underlying mechanisms are still unclear and independent of the endocannabinoid system. Therefore, we review recent advances from bench to bedside, to address the cannabinoid control on seizures, discuss the existing confusion in current studies and provide directions for further research, which may be clinically important for the design of cannabinoid-based precise therapeutic interventions for epilepsy.