Phosphorylation of PI3K/Akt at Thr308, but not phosphorylation of MAPK kinase, mediates lithium-induced neuroprotection against cerebral ischemia in mice

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dc.authorid0000-0003-0039-3281
dc.authorid0000-0002-9476-8488
dc.authorid0000-0002-6242-3709
dc.authorid0000-0003-2251-2093
dc.authorid0000-0002-5072-132X
dc.authorid0000-0002-0675-1839
dc.authorid0000-0001-6494-8923
dc.contributor.authorAteş, Nilay
dc.contributor.authorÇağlayan, Aysun
dc.contributor.authorBalçıkanlı, Zeynep
dc.contributor.authorSertel, Elif
dc.contributor.authorBeker, Mustafa Çağlar
dc.contributor.authorDilsiz, Pelin
dc.contributor.authorÇağlayan, Ahmet Burak
dc.contributor.authorÇelik, Süleyman
dc.contributor.authorDaşdelen, Muhammed Furkan
dc.contributor.authorÇağlayan, Berrak
dc.contributor.authorYiğitbaşı, Türkan
dc.contributor.authorÖzbek, Hanefi
dc.contributor.authorDoeppner, Thorsten Roland
dc.contributor.authorHermann, Dirk Matthias
dc.contributor.authorKılıç, Ertuğrul
dc.date.accessioned2022-02-28T13:55:33Z
dc.date.available2022-02-28T13:55:33Z
dc.date.issued2022
dc.departmentİstanbul Medipol Üniversitesi, Rektörlük, Sağlık Bilim ve Teknolojileri Araştırma Enstitüsü
dc.departmentİstanbul Medipol Üniversitesi, Rektörlük, Rejeneratif ve Restoratif Tıp Araştırmaları Merkezi (REMER)
dc.departmentİstanbul Medipol Üniversitesi, Tıp Fakültesi, Dahili Tıp Bilimleri Bölümü, Tıbbi Farmakoloji Ana Bilim Dalı
dc.departmentİstanbul Medipol Üniversitesi, Tıp Fakültesi, Temel Tıp Bilimleri Bölümü, Fizyoloji Ana Bilim Dalı
dc.departmentİstanbul Medipol Üniversitesi, Uluslararası Tıp Fakültesi, Temel Tıp Bilimleri Bölümü, Tıbbi Biyoloji Ana Bilim Dalı
dc.departmentİstanbul Medipol Üniversitesi, Tıp Fakültesi, Temel Tıp Bilimleri Bölümü, Tıbbi Biyokimya Ana Bilim Dalı
dc.description.abstractLithium, in addition to its effect on acute and long-term bipolar disorder, is involved in neuroprotection after ischemic stroke. Yet, its mechanism of action is still poorly understood, which was only limited to its modulatory effect on GSK pathway. Therefore, we initially analyzed the dose-dependent effects of lithium on neurological deficits, infarct volume, brain edema and blood-brain barrier integrity, along with neuronal injury and survival in mice subjected to focal cerebral ischemia. Thereafter, we investigated the involvement of the PI3K/Akt and MEK signal transduction pathways and their components. Our observations revealed that 2 mmol/kg lithium significantly improved post-ischemic brain tissue survival. Although, 2 mmol/kg lithium had no negative effect on brain microcirculation, 5 and 20 mmol/kg lithium reduced brain perfusion. Furthermore, supratherapeutic dose of lithium in 20 mmol/kg lead to animal death. In addition, improvement of brain perfusion with L-arginine, did not change the effect of 5 mmol/kg lithium on brain injury. Additionally, post-stroke blood-brain barrier leakage, hemodynamic impairment and apoptosis have been reversed by lithium treatment. Interestingly, lithium-induced neuroprotection was associated with increased phosphorylation of Akt at Thr308 and suppressed GSK-3? phosphorylation at Ser9 residue. Lithium upregulated Erk-2 and downregulated JNK-2 phosphorylation. To distinguish whether neuroprotective effects of lithium are modulated by PI3K/Akt or MEK, we sequentially blocked these pathways and demonstrated that the neuroprotective activity of lithium persisted during MEK/ERK inhibition, whereas PI3K/Akt inhibition abolished neuroprotection. Collectively, we demonstrated lithium exerts its post-stroke neuroprotective activity via the PI3K/Akt pathway, specifically via Akt phosphorylation at Thr308, but not via MEK/ERK.
dc.description.sponsorshipTurkish Academy of Sciences ; Istanbul Medipol Universityen_US
dc.identifier.citationAteş, N., Çağlayan, A., Balçıkanlı, Z., Sertel, E., Beker, M. Ç., Dilsiz, P. ... Kılıç, E. (2022). Phosphorylation of PI3K/Akt at Thr308, but not phosphorylation of MAPK kinase, mediates lithium-induced neuroprotection against cerebral ischemia in mice. Experimental Neurology, 351. https://doi.org/10.1016/j.expneurol.2022.113996
dc.identifier.doi10.1016/j.expneurol.2022.113996
dc.identifier.issn0014-4886
dc.identifier.pmid35122865
dc.identifier.scopus2-s2.0-85124136875
dc.identifier.scopusqualityQ1
dc.identifier.urihttps://doi.org/10.1016/j.expneurol.2022.113996
dc.identifier.urihttps://hdl.handle.net/20.500.12511/9032
dc.identifier.volume351
dc.identifier.wos000784293000004en_US
dc.identifier.wosqualityQ2
dc.indekslendigikaynakWeb of Science
dc.indekslendigikaynakScopus
dc.indekslendigikaynakPubMed
dc.institutionauthorAteş, Nilay
dc.institutionauthorÇağlayan, Aysun
dc.institutionauthorBalçıkanlı, Zeynep
dc.institutionauthorSertel, Elif
dc.institutionauthorBeker, Mustafa Çağlar
dc.institutionauthorDilsiz, Pelin
dc.institutionauthorÇağlayan, Ahmet Burak
dc.institutionauthorÇelik, Süleyman
dc.institutionauthorDaşdelen, Muhammed Furkan
dc.institutionauthorÇağlayan, Berrak
dc.institutionauthorYiğitbaşı, Türkan
dc.institutionauthorÖzbek, Hanefi
dc.institutionauthorDoeppner, Thorsten Roland
dc.institutionauthorKılıç, Ertuğrul
dc.language.isoen
dc.publisherAcademic Press Inc.
dc.relation.ispartofExperimental Neurologyen_US
dc.relation.publicationcategoryMakale - Uluslararası Hakemli Dergi - Kurum Öğretim Elemanı
dc.rightsinfo:eu-repo/semantics/embargoedAccess
dc.subjectFocal Cerebral Ischemia
dc.subjectLithium
dc.subjectNeuroprotection
dc.subjectPI3K Inhibition
dc.subjectPI3K/Akt Signaling Pathway
dc.titlePhosphorylation of PI3K/Akt at Thr308, but not phosphorylation of MAPK kinase, mediates lithium-induced neuroprotection against cerebral ischemia in mice
dc.typeArticle

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