Involvement of orexin type-2 receptors in genetic absence epilepsy rats
IntroductionOrexin is a neuropeptide neurotransmitter that regulates the sleep/wake cycle produced by the lateral hypothalamus neurons. Recent studies have shown the involvement of orexin system in epilepsy. Limited data is available about the possible role of orexins in the pathophysiology of absen...
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| Format: | Article |
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Frontiers Media S.A.
2023-11-01
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| Series: | Frontiers in Neurology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fneur.2023.1282494/full |
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| author | Aylin Toplu Aylin Toplu Nursima Mutlu Elif Tuğçe Erdeve Özge Sariyildiz Musa Çelik Devrim Öz-Arslan Devrim Öz-Arslan Devrim Öz-Arslan Özlem Akman Zoltan Molnár Nihan Çarçak Nihan Çarçak Filiz Onat Filiz Onat |
| author_facet | Aylin Toplu Aylin Toplu Nursima Mutlu Elif Tuğçe Erdeve Özge Sariyildiz Musa Çelik Devrim Öz-Arslan Devrim Öz-Arslan Devrim Öz-Arslan Özlem Akman Zoltan Molnár Nihan Çarçak Nihan Çarçak Filiz Onat Filiz Onat |
| author_sort | Aylin Toplu |
| collection | DOAJ |
| description | IntroductionOrexin is a neuropeptide neurotransmitter that regulates the sleep/wake cycle produced by the lateral hypothalamus neurons. Recent studies have shown the 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. The 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.MethodsThe effect of intracerebroventricular (ICV) (100, 300, and 600 nmol/10 μL), intrathalamic (30 and 40 nmol/500 nL), and intracortical (40 nmol/500 nL) microinjections of YNT-185 on the duration and number of spontaneous SWDs were evaluated in adult GAERS. The percentage of slow-wave sleep (SWS) and spectral characteristics of background EEG were analyzed after the ICV application of 600 nmol YNT-185. The level of OX2R expression in the somatosensory cortex and projecting thalamic nuclei of adult GAERS were examined by Western blot and compared with the non-epileptic Wistar rats.ResultsWe showed that ICV administration of YNT-185 suppressed the cumulative duration of SWDs in GAERS compared to the saline-administered control group (p < 0.05). However, intrathalamic and intracortical microinjections of YNT-185 did not show 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 1–2 h 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.ConclusionThis study investigated the efficacy of YNT-185 for the first time on absence epilepsy in GAERS and 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 toward understanding the effectiveness of orexin neuropeptides on absence seizures in GAERS and might be targeted by therapeutic intervention for absence epilepsy. |
| first_indexed | 2024-03-09T10:45:17Z |
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| id | doaj.art-34af1394138e4e5db5a066643e6cfa71 |
| institution | Directory Open Access Journal |
| issn | 1664-2295 |
| language | English |
| last_indexed | 2024-03-09T10:45:17Z |
| publishDate | 2023-11-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Neurology |
| spelling | doaj.art-34af1394138e4e5db5a066643e6cfa712023-12-01T10:31:51ZengFrontiers Media S.A.Frontiers in Neurology1664-22952023-11-011410.3389/fneur.2023.12824941282494Involvement of orexin type-2 receptors in genetic absence epilepsy ratsAylin Toplu0Aylin Toplu1Nursima Mutlu2Elif Tuğçe Erdeve3Özge Sariyildiz4Musa Çelik5Devrim Öz-Arslan6Devrim Öz-Arslan7Devrim Öz-Arslan8Özlem Akman9Zoltan Molnár10Nihan Çarçak11Nihan Çarçak12Filiz Onat13Filiz Onat14Department of Medical Pharmacology, School of Medicine, Marmara University, Istanbul, TürkiyeDepartment of Neuroscience, Health Sciences Institute, Acibadem Mehmet Ali Aydinlar University, Istanbul, TürkiyeDepartment of Molecular Biotechnology and Genetics, Institute of Science, Istanbul University, Istanbul, TürkiyeDepartment of Pharmacology, Health Sciences Institute, Istanbul University, Istanbul, TürkiyeDepartment of Neuroscience, Health Sciences Institute, Acibadem Mehmet Ali Aydinlar University, Istanbul, TürkiyeDepartment of Biophysics, Health Sciences Institute, Acibadem Mehmet Ali Aydinlar University, Istanbul, TürkiyeDepartment of Neuroscience, Health Sciences Institute, Acibadem Mehmet Ali Aydinlar University, Istanbul, TürkiyeDepartment of Biophysics, Health Sciences Institute, Acibadem Mehmet Ali Aydinlar University, Istanbul, TürkiyeDepartment of Biophysics, School of Medicine, Acibadem Mehmet Ali Aydinlar University, Istanbul, TürkiyeDepartment of Physiology, Faculty of Medicine, Demiroglu Bilim University, Istanbul, TürkiyeDepartment of Physiology, Anatomy and Genetics, University of Oxford, Oxford, United KingdomDepartment of Neuroscience, Health Sciences Institute, Acibadem Mehmet Ali Aydinlar University, Istanbul, TürkiyeDepartment of Pharmacology, Faculty of Pharmacy, Istanbul University, Istanbul, TürkiyeDepartment of Neuroscience, Health Sciences Institute, Acibadem Mehmet Ali Aydinlar University, Istanbul, Türkiye0Department of Medical Pharmacology, School of Medicine, Acibadem Mehmet Ali Aydinlar University, Istanbul, TürkiyeIntroductionOrexin is a neuropeptide neurotransmitter that regulates the sleep/wake cycle produced by the lateral hypothalamus neurons. Recent studies have shown the 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. The 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.MethodsThe effect of intracerebroventricular (ICV) (100, 300, and 600 nmol/10 μL), intrathalamic (30 and 40 nmol/500 nL), and intracortical (40 nmol/500 nL) microinjections of YNT-185 on the duration and number of spontaneous SWDs were evaluated in adult GAERS. The percentage of slow-wave sleep (SWS) and spectral characteristics of background EEG were analyzed after the ICV application of 600 nmol YNT-185. The level of OX2R expression in the somatosensory cortex and projecting thalamic nuclei of adult GAERS were examined by Western blot and compared with the non-epileptic Wistar rats.ResultsWe showed that ICV administration of YNT-185 suppressed the cumulative duration of SWDs in GAERS compared to the saline-administered control group (p < 0.05). However, intrathalamic and intracortical microinjections of YNT-185 did not show 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 1–2 h 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.ConclusionThis study investigated the efficacy of YNT-185 for the first time on absence epilepsy in GAERS and 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 toward understanding the effectiveness of orexin neuropeptides on absence seizures in GAERS and might be targeted by therapeutic intervention for absence epilepsy.https://www.frontiersin.org/articles/10.3389/fneur.2023.1282494/fullabsence epilepsyorexin type-2 receptorspike-and-wave dischargeYNT-185epilepsy |
| spellingShingle | Aylin Toplu Aylin Toplu Nursima Mutlu Elif Tuğçe Erdeve Özge Sariyildiz Musa Çelik Devrim Öz-Arslan Devrim Öz-Arslan Devrim Öz-Arslan Özlem Akman Zoltan Molnár Nihan Çarçak Nihan Çarçak Filiz Onat Filiz Onat Involvement of orexin type-2 receptors in genetic absence epilepsy rats Frontiers in Neurology absence epilepsy orexin type-2 receptor spike-and-wave discharge YNT-185 epilepsy |
| title | Involvement of orexin type-2 receptors in genetic absence epilepsy rats |
| title_full | Involvement of orexin type-2 receptors in genetic absence epilepsy rats |
| title_fullStr | Involvement of orexin type-2 receptors in genetic absence epilepsy rats |
| title_full_unstemmed | Involvement of orexin type-2 receptors in genetic absence epilepsy rats |
| title_short | Involvement of orexin type-2 receptors in genetic absence epilepsy rats |
| title_sort | involvement of orexin type 2 receptors in genetic absence epilepsy rats |
| topic | absence epilepsy orexin type-2 receptor spike-and-wave discharge YNT-185 epilepsy |
| url | https://www.frontiersin.org/articles/10.3389/fneur.2023.1282494/full |
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