The indirect NMDAR inhibitor flupirtine induces sustained post-ischemic recovery, neuroprotection and angioneurogenesis

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dc.authorid0000-0001-6494-8923
dc.contributor.authorJaeger, Hanna
dc.contributor.authorPehlke, Jens
dc.contributor.authorKaltwasser, Britta
dc.contributor.authorKılıç, Ertuğrul
dc.contributor.authorBaehr, Mathias
dc.contributor.authorHermann, Dirk
dc.contributor.authorDoeppner, Thorsten
dc.date.accessioned10.07.201910:49:13
dc.date.accessioned2019-07-10T20:02:14Z
dc.date.available10.07.201910:49:13
dc.date.available2019-07-10T20:02:14Z
dc.date.issued2015
dc.departmentİstanbul Medipol Üniversitesi, Rektörlük, Rejeneratif ve Restoratif Tıp Araştırmaları Merkezi (REMER)
dc.descriptionWOS: 000359010000019
dc.descriptionPubMed ID: 26050199
dc.description.abstractN-methyl-D-aspartate receptor (NMDAR) activation induces excitotoxicity, contributing to post-stroke brain injury. Hitherto, NMDAR deactivation failed in clinical trials due to insufficient pre-clinical study designs and drug toxicity. Flupirtine is an indirect NMDAR antagonist being used as analgesic in patients. Taking into account its tolerability profile, we evaluated effects of flupirtine on post-stroke tissue survival, neurological recovery and brain remodeling. Mice were exposed to stroke and intraperitoneally treated with saline (control) or flupirtine at various doses (1-10 mg/kg) and time-points (0-12 hours). Tissue survival and cell signaling were studied on day 2, whereas neurological recovery and tissue remodeling were analyzed until day 84. Flupirtine induced sustained neuroprotection, when delivered up to 9 hours. The latter yielded enhanced neurological recovery that persisted over three months and which was accompanied by enhanced angioneurogenesis. On the molecular level, inhibition of calpain activation was noted, which was associated with increased signal-transducer-and-activator-of-transcription-6 (STAT6) abundance, reduced N-terminal-Jun-kinase and NF-kappa B activation, as well as reduced proteasomal activity. Consequently, blood-brain-barrier integrity was stabilized, oxidative stress was reduced and brain leukocyte infiltration was diminished. In view of its excellent tolerability, considering its sustained effects on neurological recovery, brain tissue survival and remodeling, flupirtine is an attractive candidate for stroke therapy.
dc.description.sponsorshipTUBITAK [2221]; German Research Council [HE3173/2-2, HE3173/3-1]en_US
dc.description.sponsorshipThe present study was supported by TUBITAK (#2221 to TRD) and the German Research Council (#HE3173/2-2 and #HE3173/3-1 to DMH).en_US
dc.identifier.citationJaeger, H., Pehlke, J., Kaltwasser, B., Kılıç, E., Baehr, M., Hermann, D. ve Doeppner, T. (2015). TThe indirect NMDAR inhibitor flupirtine induces sustained post-ischemic recovery, neuroprotection and angioneurogenesis. Oncotarget, 6(16), 14033-14044. https://dx.doi.org/10.18632/oncotarget.4226
dc.identifier.doi10.18632/oncotarget.4226
dc.identifier.endpage14044
dc.identifier.issn1949-2553
dc.identifier.issue16
dc.identifier.scopusqualityQ1
dc.identifier.startpage14033
dc.identifier.urihttps://dx.doi.org/10.18632/oncotarget.4226
dc.identifier.urihttps://hdl.handle.net/20.500.12511/3592
dc.identifier.volume6
dc.identifier.wosqualityN/A
dc.indekslendigikaynakWeb of Science
dc.indekslendigikaynakScopus
dc.indekslendigikaynakPubMed
dc.language.isoen
dc.publisherImpact Journals
dc.relation.ecinfo:eu-repo/grantAgreement/TUBITAK/SOBAG/2221
dc.relation.ispartofOncotargeten_US
dc.relation.publicationcategoryMakale - Uluslararası Hakemli Dergi - Kurum Öğretim Elemanı
dc.rightsAttribution 3.0 Unported*
dc.rightsinfo:eu-repo/semantics/openAccess
dc.rights.urihttps://creativecommons.org/licenses/by/3.0/*
dc.subjectPathology
dc.subjectExcitotoxicity
dc.subjectFocal Cerebral Ischemia
dc.subjectNeuroprotection
dc.subjectN-Methyl-D-Aspartate-Receptors (NMDAR)
dc.titleThe indirect NMDAR inhibitor flupirtine induces sustained post-ischemic recovery, neuroprotection and angioneurogenesis
dc.typeArticle

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