Systemic proteasome inhibition induces sustained post-stroke neurological recovery and neuroprotection via mechanisms involving reversal of peripheral immunosuppression and preservation of blood-brain-barrier integrity

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dc.authorid0000-0001-6494-8923
dc.contributor.authorDoeppner, Thorsten Roland
dc.contributor.authorKaltwasser, Britta
dc.contributor.authorKuckelkorn, Ulrike
dc.contributor.authorHenkelein, Petra
dc.contributor.authorBretschneider, Eva
dc.contributor.authorKılıç, Ertuğrul
dc.contributor.authorHermann, Dirk M.
dc.date.accessioned10.07.201910:49:13
dc.date.accessioned2019-07-10T20:01:50Z
dc.date.available10.07.201910:49:13
dc.date.available2019-07-10T20:01:50Z
dc.date.issued2016
dc.departmentİstanbul Medipol Üniversitesi, Rektörlük, Rejeneratif ve Restoratif Tıp Araştırmaları Merkezi (REMER)
dc.descriptionWOS: 000387231300044
dc.descriptionPubMed ID: 26572637
dc.description.abstractIn view of its profound effect on cell survival and function, the modulation of the ubiquitin-proteasome-system has recently been shown to promote neurological recovery and brain remodeling after focal cerebral ischemia. Hitherto, local intracerebral delivery strategies were used, which can hardly be translated to human patients. We herein analyzed effects of systemic intraperitoneal delivery of the proteasome inhibitor BSc2118 on neurological recovery, brain injury, peripheral and cerebral immune responses, neurovascular integrity, as well as cerebral neurogenesis and angiogenesis in a mouse model of transient intraluminal middle cerebral artery occlusion. Systemic delivery of BSc2118 induced acute neuroprotection reflected by reduced infarct volume when delivered up to 9 h post-stroke. The latter was associated with reduced brain edema and stabilization of blood-brain-barrier integrity, albeit cerebral proteasome activity was only mildly reduced. Neuronal survival persisted in the post-acute stroke phase up to 28 days post-stroke and was associated with improved neurological recovery when the proteasome inhibitor was continuously delivered over 7 days. Systemic proteasome inhibition prevented stroke-induced acute leukocytosis in peripheral blood and reversed the subsequent immunosuppression, namely, the reduction of blood lymphocyte and granulocyte counts. On the contrary, post-ischemic brain inflammation, cerebral HIF-1 alpha abundance, cell proliferation, neurogenesis, and angiogenesis were not influenced by the proteasome inhibitor. The modulation of peripheral immune responses might thus represent an attractive target for the clinical translation of proteasome inhibitors.
dc.description.sponsorshipGerman Research Council (DFG) [HE3173/2-2, HE3173/3-1]; Scientific and Technological Research Council of Turkey (TUBITAK) [2221]en_US
dc.description.sponsorshipThis study was supported by grants from the German Research Council (DFG, No. HE3173/2-2 and No. HE3173/3-1 to DMH) and a grant from the Scientific and Technological Research Council of Turkey (TUBITAK, No. 2221 to TRD).en_US
dc.identifier.citationDoeppner, T. R., Kaltwasser, B., Kuckelkorn, U., Henkelein, P., Bretschneider, E., Kılıç, E. ... Hermann, D. M. (2016). Systemic proteasome inhibition induces sustained post-stroke neurological recovery and neuroprotection via mechanisms involving reversal of peripheral immunosuppression and preservation of blood-brain-barrier integrity. Molecular Neurobiology, 53(9), 6332-6341. https://dx.doi.org/10.1007/s12035-015-9533-3
dc.identifier.doi10.1007/s12035-015-9533-3
dc.identifier.endpage6341
dc.identifier.issn0893-7648
dc.identifier.issn1559-1182
dc.identifier.issue9
dc.identifier.scopusqualityQ1
dc.identifier.startpage6332
dc.identifier.urihttps://dx.doi.org/10.1007/s12035-015-9533-3
dc.identifier.urihttps://hdl.handle.net/20.500.12511/3463
dc.identifier.volume53
dc.identifier.wosqualityQ1
dc.indekslendigikaynakWeb of Science
dc.indekslendigikaynakScopus
dc.indekslendigikaynakPubMed
dc.language.isoen
dc.publisherSpringer
dc.relation.ispartofMolecular Neurobiologyen_US
dc.relation.publicationcategoryMakale - Uluslararası Hakemli Dergi - Kurum Öğretim Elemanı
dc.rightsinfo:eu-repo/semantics/openAccess
dc.subjectCerebral Ischemia
dc.subjectStroke
dc.subjectProteasome
dc.subjectNeuroprotection
dc.subjectNeuroregeneration
dc.subjectInflammation
dc.titleSystemic proteasome inhibition induces sustained post-stroke neurological recovery and neuroprotection via mechanisms involving reversal of peripheral immunosuppression and preservation of blood-brain-barrier integrity
dc.typeArticle

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