The Effect of Rapamycin on Penicillin- Induced Epileptiform Activity in Rats: An Electrophysiological Study/Rapamisinin Sıçanlarda Penisilinle Oluşturulmuş Epileptiform Aktivite Üzerine Etkisi: Bir Elektrofizyolojik Çalışma

Abstract Aim: Approximately fifty million people in the world suffer from epilepsy, and a large part of these patients are resistant to antiepileptic drugs discovered so far. In addition, side effect profiles of these drugs are very wide. Rapamycin that is an inhibitor of mammalian target of rapamycin (mTOR) has antineoplastic, aging-retarding, and anti-inflammatory effects. The studies regarding the effects of mTOR on nervous system have shown that it has neuro-protective effects. Moreover, it has been reported that use of rapamycin reduces epileptic seizures in tuberous sclerosis patients. In this study we aimed to investigate acute effects of the mTOR inhibitor rapamycin on penicillin-induced experimental epilepsy in rats. Materials and Methods: In this study, a model of forty adult male Wistar rats with penicillininduced experimental epilepsy was used. The forty rats were divided into five groups, which were saline group, solvent (dimethylsulfoxide) group, and 0.1 mg/kg, 0.4 mg/kg and 0.8 mg/kg rapamycin groups. All substances were administered intraperitoneally. After the administration of 1.25 g/kg urethane for anesthesia, the left part of each rat’s skull was opened and electrodes were placed on the brain. Electrocorticography recording was initiated. Penicillin was intracortically administered two hours after the administration of rapamycin. After the administration of penicillin, electrocorticographic data were recorded for another two hours. Results: In rapamycin-treated rat groups, administration of 0.4 mg/kg and 0.8 mg/kg rapamycin significantly reduced epileptic spike-wave frequency and amplitude of epileptiform activity. However, when compared in terms of latency no significant difference was found between the groups. Discussion and Conclusion: Acute administration of rapamycin reduced spike-wave frequency and spike-wave amplitude of penicillin-induced epileptiform activity in the rats, and these findings indicate that rapamycin has an antiepileptogenic potential. Keywords: rapamycin; mTOR; epileptiform activity; electrocorticography; rat Ozet Amac: Yeryuzunde yaklasik elli milyon insan epilepsinin pencesindedir ve bu hastalarin buyuk bir bolumu simdiye kadar kesfedilmis antiepileptik ilaclara karsi direnclidir. Bunun yani sira, bu ilaclarin yan etki profilleri de oldukca genistir. Memelideki rapamisin hedefi (mTOR) inhibitoru olan rapamisin; antineoplastik, yaslanmayi geciktirici ve antienflamatuvar etkilere sahiptir. mTOR’un sinir sistemi uzerindeki etkilerine dair calismalarda ise noroprotektif etkisinin oldugu gosterilmistir. Buna ek olarak, tuberoskleroz hastalarinda rapamisin kullaniminin epileptik nobetleri azalttigi bildirilmistir. Bu calismanin amaci mTOR inhibitoru rapamisinin sicanlarda penisilinle olusturulmus deneysel epilepsi uzerindeki akut etkisini arastirmaktir. Gerec ve Yontemler: Bu calismada penisilinle olusturulmus deneysel epilepsili kirk adet eriskin erkek Wistar sican iceren bir model kullanilmistir. Soz konusu kirk sican; salin, cozucu (dimetilsulfoksit), ve de 0,1 mg/kg, 0,4 mg/kg ve 0,8 mg/kg rapamisin gruplari olmak uzere bes grubaayrildi. Tum maddeler intraperitoneal yolla uygulandi. Sicanlara anestezi icin 1,25 g/kg uretan uygulandiktan sonra hayvanlarin sol kafatasi acildi ve beyin uzerine elektrotlar yerlestirildi. Elektrokortikografi kaydi baslatildi. Rapamisin uygulamasindan iki saat sonra intrakortikal olarak penisilin uygulandi. Penisilin uygulandiktan sonra elektrokortikografi verileri iki saat daha kaydedildi. Bulgular: Rapamisinle tedavi edilen sican gruplarinda, 0,4 mg/kg ve 0,8 mg/kg rapamisin uygulamalari epileptiform aktivitenin diken-dalga sikligini ve genligini anlamli olarak azaltmistir. Fakat latensleri karsilastirildiginda gruplar arasinda anlamli bir fark bulunmamistir. Tartisma ve Sonuc: Akut rapamisin uygulamasi sicanlarda penisilinle olusturulmus epileptiform aktivitenin diken-dalga sikligini ve diken-dalga genligini azaltmistir ve bu bulgular rapamisinin antiepileptojenik bir potansiyele sahip oldugunu gostermektedir. Anahtar Sozcukler: rapamisin; mTOR; epileptiform aktivite; elektrokortikografi; sican