title: 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.
abstract: In 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-1α 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.
authors.affiliation: Department of Neurology, University of Duisburg-Essen, Essen, Germany. thorsten.doeppner@uk-essen.de.|Regenerative and Restorative Medical Research Center, Istanbul Medipol University, Istanbul, Turkey. thorsten.doeppner@uk-essen.de.
authors.forename: Thorsten R
authors.initials: TR
authors.lastname: Doeppner
authors.affiliation: Department of Neurology, University of Duisburg-Essen, Essen, Germany.
authors.forename: Britta
authors.initials: B
authors.lastname: Kaltwasser
authors.affiliation: Department of Biochemistry, Charité-Universitätsmedizin, Berlin, Germany.
authors.forename: Ulrike
authors.initials: U
authors.lastname: Kuckelkorn
authors.affiliation: Department of Biochemistry, Charité-Universitätsmedizin, Berlin, Germany.
authors.forename: Petra
authors.initials: P
authors.lastname: Henkelein
authors.affiliation: Department of Otorhinolaryngology, Johannes Wesling Klinikum, Minden, Germany.
authors.forename: Eva
authors.initials: E
authors.lastname: Bretschneider
authors.affiliation: Regenerative and Restorative Medical Research Center, Istanbul Medipol University, Istanbul, Turkey.
authors.forename: Ertugrul
authors.initials: E
authors.lastname: Kilic
authors.affiliation: Department of Neurology, University of Duisburg-Essen, Essen, Germany.
authors.forename: Dirk M
authors.initials: DM
authors.lastname: Hermann
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000473:pathology* / Q000503:physiopathology; D002545:Brain Ischemia / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology; D002073:Butanes / Q000494:pharmacology / Q000627:therapeutic use; D016503:Drug Delivery Systems; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D007165:Immunosuppression Therapy; D007964:Leukocytosis / Q000150:complications / Q000188:drug therapy / Q000473:pathology; D008297:Male; D008810:Mice, Inbred C57BL; D018919:Neovascularization, Physiologic / Q000187:drug effects; D000066829:Neuroprotection / Q000187:drug effects; D009842:Oligopeptides / Q000494:pharmacology / Q000627:therapeutic use; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D061988:Proteasome Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D020127:Recovery of Function / Q000187:drug effects; D020521:Stroke / Q000150:complications / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology*
chemical_list: C513723:BSc2118; D002073:Butanes; C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009842:Oligopeptides; D061988:Proteasome Inhibitors; D046988:Proteasome Endopeptidase Complex
keywords: Cerebral ischemia; Inflammation; Neuroprotection; Neuroregeneration; Proteasome; Stroke