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dc.contributor.advisorSara, Mehmet Yıldırım
dc.contributor.authorBayraktar, Erva
dc.date.accessioned2020-10-12T08:32:48Z
dc.date.issued2020
dc.date.submitted2020-09-22
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dc.identifier.urihttp://hdl.handle.net/11655/22903
dc.description.abstractMajor problems with the current anti-epileptic drugs (AED) are resistance, inability to modify the course of the disease and side effects profiles, which rises the need for improved AEDs for all age group of patients. Eslicarbazepine acetate is a sodium channel blocker AED and is superior to some other well-known AEDs in terms of selectivity, safety, efficacy and effects on sodium channels. In our study, to assess eslicarbazepine (S-Lic) effects, we chose wild-type Nav1.6 channels along with three SCN8A gene variants known to be causing developmental and epileptic encephalopathies (DEE), (M1760I, G1475R, and A1622D). Electrophysiological analyses were performed by using two heterologous expression systems (neuroblastoma cell line (ND7/23) for voltage-clamp recordings, and primary neuronal cultures for current-clamp recordings). 300 μM of S-Lic reduced maximal firing rates in neurons having wild-type NaV1.6 channels. S-Lic enhanced slow inactivation kinetics in all DEE variants tested, but also displayed variant-specific effects by modifying biophysical properties of tested variant channels. S-Lic treatment increased the kinetics of fast inactivation and reduced the persistent current in A1622D variant. Additionally, S-Lic decreased neuronal firing rate to that of wild-type in M1760I variant. Those findings emphasize the significance of individualized therapy, and prompt the potential use of Eslicarbazepine acetate, -taking into account its unique effects on epileptogenesis and slow inactivation, and its better safety and therapeutic index – as an alternative option against some SCN8A (NaV1.6) variants causing DEE.tr_TR
dc.language.isoentr_TR
dc.publisherSağlık Bilimleri Enstitüsütr_TR
dc.rightsinfo:eu-repo/semantics/openAccesstr_TR
dc.subjectEpilepsytr_TR
dc.subjectDevelopmental and Epileptic encephalopathiestr_TR
dc.subjectEslicarbazepine acetatetr_TR
dc.subjectNav1.6tr_TR
dc.subjectSodium channel blockerstr_TR
dc.subjectVoltage-clamptr_TR
dc.subjectCurrent-clamptr_TR
dc.titleElectrophysiological Effects of Eslicarbazepine on Selected Nav1.6 Variants Associated with Developmental and Epileptic Encephalopathiestr_TR
dc.typeinfo:eu-repo/semantics/doctoralThesistr_TR
dc.description.ozetGünümüz kullanımında yer alan antiepileptik ilaçların (AEİ) direnç gelişimi, hastalık seyrini modifiye etmedeki yetersizliği ve yan etki profilinin geniş olması gibi problemlerinin bulunması tüm yaş gruplarındaki hastalarda daha gelişmiş AEİ seçeneklerine ihtiyacı doğurmaktadır. Eslikarbazepin asetat sodyum kanal blokajı yapan bir AEİ olup seçicilik, güvenlilik, etkililik ve sodyum kanallarına etki açılarından iyi bilinen diğer sodyum kanal blokörü AEİ’lere nazaran daha üstündür. Çalışmamızda eslikarbazepinin (S-Lic) etkilerini incelemek amacıyla yabanıl tip Nav1.6 kanallarınının yanı sıra gelişimsel ve epileptik ensefalopatilere (GEE) neden olduğu bilinen üç farklı SCN8A gen varyantı (M1760I, G1475R ve A1622D) seçilmiştir. Seçilen varyantlarda elektrofizyolojik çalışmalar iki heterolog ekspresyon sisteminde gerçekleştirildi (voltaj kenetleme kayıtları için neuroblastom hücre serileri (ND7/23), akım kenetleme kayıtları için primer nöron kültürleri). 300 μM S-Lic yabanıl tip NaV1.6 kanallarına sahip nöronlarda maksimum ateşleme hızını azalttı. S-Lic yavaş inaktivasyon kinetiğini test edilen tüm GEE varyantlarında güçlendirdi, aynı zamanda test edilen bazı varyant kanallarının biyofiziksel özelliklerini modifiye ederek varyant spesifik etkiler gösterdi. S-Lic tedavisi A1622D varyantında hızlı inaktivasyon kinetiklerini artırırken kalıcı akımı azalttı. Ek olarak, S-Lic M1760I varyantında nöronal ateşleme hızını yabanıl tip seviyesine indirdi. Bu bulgular kişiselleştirilmiş tedavinin önemini vurgulamanın yanında; epileptogenez ve yavaş inaktivasyon üzerine benzersiz etkisi, terapötik indeks genişliği ve güvenliliği ile eslikarbazepin asetatın GEE’ye neden olan bazı SCN8A varyantlarında alternatif tedavi olarak kullanılmasını desteklemektedir.tr_TR
dc.contributor.departmentTıbbi Farmakolojitr_TR
dc.embargo.terms6 aytr_TR
dc.fundingDiğertr_TR


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