Phosphodiesterase 10A is a critical target for neuroprotection in a mouse model of ischemic stroke

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dc.authorid0000-0002-9476-8488
dc.authorid0000-0002-6242-3709
dc.authorid0000-0002-4051-2559
dc.authorid0000-0002-6637-9944
dc.authorid0000-0003-3616-1204
dc.authorid0000-0002-5072-132X
dc.authorid0000-0001-6494-8923
dc.contributor.authorBeker, Mustafa Çağlar
dc.contributor.authorÇağlayan, Ahmet Burak
dc.contributor.authorAltunay, Serdar
dc.contributor.authorÖzbay, Elif
dc.contributor.authorAteş, Nilay
dc.contributor.authorKeleştemur, Taha
dc.contributor.authorÇağlayan, Berrak
dc.contributor.authorKılıç, Ülkan
dc.contributor.authorDoeppner, Thorsten Roland
dc.contributor.authorHermann, Dirk Matthias
dc.contributor.authorKılıç, Ertuğrul
dc.date.accessioned2023-01-05T12:15:29Z
dc.date.available2023-01-05T12:15:29Z
dc.date.issued2022
dc.departmentİstanbul Medipol Üniversitesi, Tıp Fakültesi, Temel Tıp Bilimleri Bölümü, Fizyoloji Ana Bilim Dalı
dc.departmentİstanbul Medipol Üniversitesi, Rektörlük, Rejeneratif ve Restoratif Tıp Araştırmaları Merkezi (REMER)
dc.departmentİstanbul Medipol Üniversitesi, Rektörlük, Sağlık Bilim ve Teknolojileri Araştırma Enstitüsü
dc.departmentİstanbul Medipol Üniversitesi, Uluslararası Tıp Fakültesi, Temel Tıp Bilimleri Bölümü, Fizyoloji Ana Bilim Dalı
dc.departmentİstanbul Medipol Üniversitesi, Uluslararası Tıp Fakültesi, Dahili Tıp Bilimleri Bölümü, Tıbbi Genetik Ana Bilim Dalı
dc.description.abstractPhosphodiesterase 10A (PDE10A) hydrolyzes adenosine 3 ',5 '-cyclic monophosphate (cAMP) and guanosine 3 ',5 '-cyclic monophosphate (cGMP). It is highly expressed in the striatum. Recent evidence implied that PDE10A may be involved in the inflammatory processes following injury, such as ischemic stroke. Its role in ischemic injury was unknown. Herein, we exposed mice to 90 or 30-min middle cerebral artery occlusion, followed by the delivery of the highly selective PDE10A inhibitor TAK-063 (0.3 mg/kg or 3 mg/kg) immediately after reperfusion. Animals were sacrificed after 24 or 72 h, respectively. Both TAK-063 doses enhanced neurological function, reduced infarct volume, increased neuronal survival, reduced brain edema, and increased blood-brain barrier integrity, alongside cerebral microcirculation improvements. Post-ischemic neuroprotection was associated with increased phosphorylation (i.e., activation) of pro-survival Akt, Erk-1/2, GSK-3 alpha/beta and anti-apoptotic Bcl-xL abundance, decreased phosphorylation of pro-survival mTOR, and HIF-1 alpha, MMP-9 and pro-apoptotic Bax abundance. Interestingly, PDE10A inhibition reduced inflammatory cytokines/chemokines, including IFN-gamma and TNF-alpha, analyzed by planar surface immunoassay. In addition, liquid chromatography-tandem mass spectrometry revealed 40 proteins were significantly altered by TAK-063. Our study established PDE10A as a target for ischemic stroke therapy.
dc.description.sponsorshipTurkish Academy of Sciencesen_US
dc.identifier.citationBeker, M. Ç., Çağlayan, A. B., Altunay, S., Özbay, E., Ateş, N., Keleştemur, T. ... Kılıç, E. (2022). Phosphodiesterase 10A is a critical target for neuroprotection in a mouse model of ischemic stroke. Molecular Neurobiology, 59(1), 574-589. https://dx.doi.org/10.1007/s12035-021-02621-5
dc.identifier.doi10.1007/s12035-021-02621-5
dc.identifier.endpage589
dc.identifier.issn0893-7648
dc.identifier.issn1559-1182
dc.identifier.issue1
dc.identifier.pmid34735672
dc.identifier.scopus2-s2.0-85118575460
dc.identifier.scopusqualityQ1
dc.identifier.startpage574
dc.identifier.urihttps://dx.doi.org/10.1007/s12035-021-02621-5
dc.identifier.urihttps://hdl.handle.net/20.500.12511/10248
dc.identifier.volume59
dc.identifier.wos000714490000001en_US
dc.identifier.wosqualityQ2
dc.indekslendigikaynakWeb of Science
dc.indekslendigikaynakScopus
dc.indekslendigikaynakPubMed
dc.institutionauthorBeker, Mustafa Çağlar
dc.institutionauthorÇağlayan, Ahmet Burak
dc.institutionauthorAltunay, Serdar
dc.institutionauthorÖzbay, Elif
dc.institutionauthorAteş, Nilay
dc.institutionauthorKeleştemur, Taha
dc.institutionauthorÇağlayan, Berrak
dc.institutionauthorKılıç, Ertuğrul
dc.language.isoen
dc.publisherSpringer
dc.relation.ispartofMolecular Neurobiologyen_US
dc.relation.publicationcategoryMakale - Uluslararası Hakemli Dergi - Kurum Öğretim Elemanı
dc.relation.tubitakinfo:eu-repo/grantAgreement/TUBITAK/SOBAG/218S453
dc.rightsinfo:eu-repo/semantics/closedAccess
dc.subjectcAMP
dc.subjectFocal Cerebral Ischemia
dc.subjectInflammation
dc.subjectPDE10A
dc.subjectPhosphodiesterase
dc.subjectTAK-063
dc.titlePhosphodiesterase 10A is a critical target for neuroprotection in a mouse model of ischemic stroke
dc.typeArticle

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