The role of the orexin system in the bidirectional relation between sleep and epilepsy: new chances for patients with epilepsy by the antagonism to orexin receptors?

Epilepsy is a common neurological disorder, affecting patients of all ages, reducing the quality of life and associated with several comorbidities. Sleep impairment is a frequent condition in patients with epilepsy (PWE), and the relation between sleep and epilepsy has been considered bidirectional since one can significantly influence the other, and vice versa. The orexin system has been described more than 20 years ago and is implicated in several neuro-biological functions, other than in controlling the sleep-wake cycle. Considering the relation between epilepsy and sleep, and the significant contribution of the orexin system in regulating the sleep-wake cycle, it is conceivable that the orexin system may be affected in PWE. Preclinical studies investigated the impact of orexin system on epileptogenesis and the effect of orexin antagonism on seizures in animal models. Conversely, clinical studies are few and propose heterogeneous results also considering the different methodological approaches to orexin levels quantification (cerebrospinal-fluid or blood samples). Since the orexin system activity can be modulated by sleep, and considering the sleep impairment documented in PWE, the recently approved dual orexin receptor antagonists (DORAs) have been hypothesized for treating sleep impairment and insomnia in PWE. Accordingly, sleep improvement can be a therapeutic strategy for reducing seizure and better managing epilepsy. The present review analyses the preclinical and clinical evidence linking the orexin system to epilepsy, and hypothesizes a model in which the antagonism to the orexin system by DORAs can improve epilepsy by both a direct and a sleep-mediated (indirect) effect.