EEC 2022 | Orexin as a promising therapeutic target in epilepsy

Kristina A Simeone, PhD, Creighton University, Omaha, NE, outlines the evidence available on orexin as a therapeutic target in epilepsy. Two preclinical studies have shown that seizures are promoted and worsened upon orexin injection into the brain. Therefore, Dr Simeone’s lab investigated whether blocking orexin would reduce seizures in Kcna1-null mice. The first piece of evidence came from subdural recordings and depth electrode recordings in the lateral hypothalamus, whereby they observed that severe seizures recorded at the cortex propagated down to the lateral hypothalamus, the site of orexin production. Additionally, histology studies have shown an increase in the number of orexin-expressing neurons and an elevated orexin signal in Kcna1-null mice when compared to wild-type controls. Lastly, blocking the orexin receptor acutely via dual orexin receptor antagonists (DORAs) protected 50% of subjects against induced seizures and any seizures recorded were less severe. Preclinical studies are continuing to explore other neurological diseases to see if targeting orexin receptor 1 or orexin receptor 2 independently would have a better outcome. This interview took place at the European Epilepsy Congress (EEC) 2022.