AUTHOR=Toplu Aylin , Mutlu Nursima , Erdeve Elif Tuğçe , Sariyildiz Özge , Çelik Musa , Öz-Arslan Devrim , Akman Özlem , Molnár Zoltan , Çarçak Nihan , Onat Filiz 

TITLE=Involvement of orexin type-2 receptors in genetic absence epilepsy rats

JOURNAL=Frontiers in Neurology

VOLUME=Volume 14 - 2023

YEAR=2023

URL=https://www.frontiersin.org/journals/neurology/articles/10.3389/fneur.2023.1282494

DOI=10.3389/fneur.2023.1282494

ISSN=1664-2295

ABSTRACT=Introduction: Orexin is a neuropeptide neurotransmitter that regulates sleep/wake cycle produced from the lateral hypothalamus neurons. Recent evidences have shown involvement of orexin system in epilepsy. Limited data is available about the possible role of orexins in the pathophysiology of absence seizures. This study aims to understand the role of orexinergic signaling through the orexin-type 2 receptor (OX2R) in the pathophysiology of absence epilepsy. Pharmacological effect of a selective OX2R agonist, YNT-185 on spike-and-wave-discharges (SWDs) and the OX2R receptor protein levels in the cortex and thalamus in adult GAERS were investigated. 
Methods: The effect of intracerebroventricular (ICV) (100, 300 and 600 nmol/10µL), intrathalamic (30 and 40 nmol/500nL) and intracortical (40 nmol/500nL) microinjections of YNT-185 on the duration and number of spontaneous SWDs were evaluated in adult GAERS. Percentage of slow-wave sleep (SWS) and spectral characteristics of background EEG  were analysed after the ICV application of 600 nmol YNT-185. The level of OX2R expression in somatosensory cortex and projecting thalamic nuclei of adult GAERS were examined by Western blot and compared with the non-epileptic Wistar rats. 
Results: We showed that ICV administration of YNT-185 suppressed the cumulative duration of SWDs in GAERS compared to the saline administrated control group (p<0.05). However, intrathalamic and intracortical microinjectios of YNT-185 did not showed a significant effect on SWDs. ICV microinjections of YNT-185 affect sleep states by increasing the percentage of SWS and showed a significant treatment effect on the 1-4 Hz delta frequency band power during the 1-2hour post-injection period where YNT-185 significantly decreased the SWDs. OXR2 protein levels were significantly reduced in the cortex and thalamus of GAERS when compared to Wistar rats. 
Conclusion: This study investigated the efficacy of YNT-185 for the first time on absence epilepsy in GAERS revealed a suppressive effect of OX2R agonist on SWDs as evidenced by the significantly reduced expression of OX2R in the cortex and thalamus.  YNT-185 effect on SWDs could be attributed to its regulation of wake/sleep states. The results constitute a step towards understanding the effectiveness of orexin neuropeptides on absence seizures in GAERS and might be targeted by therapeutic intervention for absence epilepsy.