The indirect NMDAR antagonist acamprosate induces postischemic neurologic recovery associated with sustained neuroprotection and neuroregeneration

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dc.authorid0000-0001-6494-8923
dc.contributor.authorDoeppner, Thorsten Roland
dc.contributor.authorPehlke, Jens
dc.contributor.authorKaltwasser, Britta
dc.contributor.authorSchlechter, Jana
dc.contributor.authorKılıç, Ertuğrul
dc.contributor.authorBaehr, Mathias
dc.contributor.authorHermann, Dirk Matthias
dc.date.accessioned10.07.201910:49:13
dc.date.accessioned2019-07-10T19:57:35Z
dc.date.available10.07.201910:49:13
dc.date.available2019-07-10T19:57:35Z
dc.date.issued2015
dc.departmentİstanbul Medipol Üniversitesi, Rektörlük, Rejeneratif ve Restoratif Tıp Araştırmaları Merkezi (REMER)
dc.descriptionWOS: 000365891300021
dc.descriptionPubMed ID: 26219600
dc.description.abstractCerebral ischemia stimulates N-methyl-D-aspartate receptors (NMDARs) resulting in increased calcium concentration and excitotoxicity. Yet, deactivation of NMDAR failed in clinical studies due to poor preclinical study designs or toxicity of NMDAR antagonists. Acamprosate is an indirect NMDAR antagonist used for patients with chronic alcohol dependence. We herein analyzed the therapeutic potential of acamprosate on brain injury, neurologic recovery and their underlying mechanisms. Mice were exposed to cerebral ischemia, treated with intraperitoneal injections of acamprosate or saline (controls), and allowed to survive until 3 months. Acamprosate yielded sustained neuroprotection and increased neurologic recovery when given no later than 12 hours after stroke. The latter was associated with increased postischemic angioneurogenesis, albeit acamprosate did not stimulate angioneurogenesis itself. Rather, increased angioneurogenesis was due to inhibition of calpain-mediated pro-injurious signaling cascades. As such, acamprosate-mediated reduction of calpain activity resulted in decreased degradation of p35, increased abundance of the pro-survival factor STAT6, and reduced N-terminal-Jun-kinase activation. Inhibition of calpain was associated with enhanced stability of the blood-brain barrier, reduction of oxidative stress and cerebral leukocyte infiltration. Taken into account its excellent tolerability, its sustained effects on neurologic recovery, brain tissue survival, and neural remodeling, acamprosate is an intriguing candidate for adjuvant future stroke treatment.
dc.description.sponsorshipTUBITAK [2221]; German Research Council [HE3173/2-2, HE3173/3-1]en_US
dc.description.sponsorshipThis study was supported by TUBITAK (grant #2221 to TRD) and the German Research Council (grant numbers #HE3173/2-2 and #HE3173/3-1 to DMH).en_US
dc.identifier.citationDoeppner, T. R., Pehlke, J., Kaltwasser, B., Schlechter, J., Kılıç, E., Baehr, M. ve Hermann, D. M. (2015). The indirect NMDAR antagonist acamprosate induces postischemic neurologic recovery associated with sustained neuroprotection and neuroregeneration. Journal of Cerebral Blood Flow and Metabolism, 35(12), 2089-2097. https://dx.doi.org/10.1038/jcbfm.2015.179
dc.identifier.doi10.1038/jcbfm.2015.179
dc.identifier.endpage2097
dc.identifier.issn0271-678X
dc.identifier.issn1559-7016
dc.identifier.issue12
dc.identifier.scopusqualityQ1
dc.identifier.startpage2089
dc.identifier.urihttps://dx.doi.org/10.1038/jcbfm.2015.179
dc.identifier.urihttps://hdl.handle.net/20.500.12511/3007
dc.identifier.volume35
dc.identifier.wosqualityQ1
dc.indekslendigikaynakWeb of Science
dc.indekslendigikaynakScopus
dc.indekslendigikaynakPubMed
dc.language.isoen
dc.publisherNature Publishing Group
dc.relation.ispartofJournal of Cerebral Blood Flow and Metabolismen_US
dc.relation.publicationcategoryMakale - Uluslararası Hakemli Dergi - Kurum Öğretim Elemanı
dc.rightsinfo:eu-repo/semantics/openAccess
dc.subjectAnimal Models
dc.subjectCasic Science
dc.subjectBrain Ischemia
dc.subjectExcitotoxicity
dc.subjectFocal Ischemia
dc.subjectNeuroregeneration
dc.titleThe indirect NMDAR antagonist acamprosate induces postischemic neurologic recovery associated with sustained neuroprotection and neuroregeneration
dc.typeArticle

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