HMG-CoA reductase inhibitor rosuvastatin improves abnormal brain electrical activity via mechanisms involving eNOS

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dc.authorid0000-0002-6895-8560
dc.authorid0000-0002-5072-132X
dc.authorid0000-0002-6242-3709
dc.authorid0000-0001-6494-8923
dc.authorid0000-0001-6494-8923
dc.contributor.authorŞeker, Fatma Burcu
dc.contributor.authorKılıç, Ülkan
dc.contributor.authorÇa?layan, Berrak
dc.contributor.authorEthemoğlu, Muhsine Sinem
dc.contributor.authorÇağlayan, Ahmet Burak
dc.contributor.authorEkimci, Nur
dc.contributor.authorDemirci, Selami
dc.contributor.authorDo?an, Ayşegül
dc.contributor.authorÖztezcan, Serdar
dc.contributor.authorŞahin, Fikrettin
dc.contributor.authorYılmaz, Bayram
dc.contributor.authorKılıç, Ertuğrul
dc.date.accessioned10.07.201910:49:13
dc.date.accessioned2019-07-10T20:02:01Z
dc.date.available10.07.201910:49:13
dc.date.available2019-07-10T20:02:01Z
dc.date.issued2015
dc.departmentİstanbul Medipol Üniversitesi, Tıp Fakültesi, Temel Tıp Bilimleri Bölümü, Fizyoloji Ana Bilim Dalı
dc.descriptionWOS: 000346243100032
dc.descriptionPubMed ID: 25453767
dc.description.abstractApart from its repressing effect on plasma lipid levels, 3-hydroxy-3-methyl glutaryl coenzyme A (HMG-CoA) reductase inhibitors exert neuroprotective functions in animal models of neurodegenerative disorders. In view of these promising observations, we were interested in whether HMG-CoA reductase inhibition would affect epileptiform activity in the brain. To elucidate this issue, atorvastatin, simvastatin and rosuvastatin were administered orally at a dose of 20 mg/kg each for 3 days and their anti-epileptic activities were tested and compared in rats. Epileptiform activity in the brain was induced by an intracortical penicillin G injection. Among HMG-CoA reductase inhibitors, simvastatin-treatment was less effective in terms of spike frequency as compared with atorvastatin- and rosuvastatin-treated animals. Atorvastatin treatment reduced spike frequencies and amplitudes significantly throughout the experiment. However, the most pronounced anti-epileptic effect was observed in rosuvastatin-treated animals, which was associated with improved blood-brain barrier (BBB) integrity, increased expression of endothelial nitric oxide synthase (eNOS) mRNA and decreased expressions of pro-apoptotic p53, Bax and caspase-3 mRNAs. Inhibition of eNOS activity with L-NG-Nitroarginine Methyl Ester (L-NAME) reversed the anti-epileptic effect of rosuvastatin significantly. However, L-NAME did not alter the effect of rosuvastatin on the levels of p53, Bax and caspase-3 mRNA expression. Here, we provide evidence that among HMG-CoA reductase inhibitors, rosuvastatin was the most effective statin on the reduction of epileptiform activity, which was associated with improved BBB permeability, increased expression of eNOS and decreased expressions of pro-apoptotic p53, Bax and caspase-3. Our observation also revealed that the anti-epileptic effect of rosuvastatin was dependent on the increased expression level of eNOS. The robust anti-epileptic effect encourages proof-of-concept studies with rosuvastatin in human epilepsy patients with hypercholesterolemia.
dc.description.sponsorshipEuropean Molecular Biology Organization (EMBO); Turkish Academy of Sciences (TUBA/GEBIP)en_US
dc.description.sponsorshipThis work was supported by European Molecular Biology Organization (EMBO) (installation grant) and Turkish Academy of Sciences (TUBA/GEBIP).en_US
dc.identifier.citationŞeker, F. B., Kılıç, Ü., Ça?layan, B., Ethemoğlu, M. S., Çağlayan, A. B., Ethemoğlu, M. S. ... Kılıç, E. (2015). HMG-CoA reductase inhibitor rosuvastatin improves abnormal brain electrical activity via mechanisms involving eNOS. Neuroscience, 284, 349-359. https://dx.doi.org/10.1016/j.neuroscience.2014.10.014
dc.identifier.doi10.1016/j.neuroscience.2014.10.014
dc.identifier.endpage359
dc.identifier.issn0306-4522
dc.identifier.issn1873-7544
dc.identifier.scopusqualityQ2
dc.identifier.startpage349
dc.identifier.urihttps://dx.doi.org/10.1016/j.neuroscience.2014.10.014
dc.identifier.urihttps://hdl.handle.net/20.500.12511/3524
dc.identifier.volume284
dc.identifier.wosqualityQ3
dc.indekslendigikaynakWeb of Science
dc.indekslendigikaynakScopus
dc.indekslendigikaynakPubMed
dc.language.isoen
dc.publisherElsevier
dc.relation.ispartofNeuroscienceen_US
dc.relation.publicationcategoryMakale - Uluslararası Hakemli Dergi - Kurum Öğretim Elemanı
dc.rightsinfo:eu-repo/semantics/embargoedAccess
dc.subjectHMG-CoA Reductase
dc.subjectRosuvastatin
dc.subjecteNOS
dc.subjectEpilepsy
dc.subjectGene Expression
dc.titleHMG-CoA reductase inhibitor rosuvastatin improves abnormal brain electrical activity via mechanisms involving eNOS
dc.typeArticle

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