title: Ischemic Post-Conditioning Induces Post-Stroke Neuroprotection via Hsp70-Mediated Proteasome Inhibition and Facilitates Neural Progenitor Cell Transplantation.
abstract: In view of the failure of pharmacological therapies, alternative strategies promoting post-stroke brain repair are needed. Post-conditioning is a potentially promising therapeutic strategy, which induces acute neuroprotection against ischemic injury. To elucidate longer lasting actions of ischemic post-conditioning, mice were exposed to a 60-min stroke and post-conditioning by an additional 10-min stroke that was induced 10 min after reperfusion onset. Animals were sacrificed 24 h or 28 days post-stroke. Post-conditioning reduced infarct volume and neurological deficits 24 h post-stroke, enhancing blood-brain barrier integrity, reducing brain leukocyte infiltration, and reducing oxidative stress. On the molecular level, post-conditioning yielded increased Hsp70 expression, whereas nuclear factor (NF)-κB and proteasome activities were decreased. Reduced infarct volume and proteasome inhibition were reversed by Hsp70 knockdown, suggesting a critical role of the Hsp70 proteasome pathway in ischemic post-conditioning. The survival-promoting effects of ischemic post-conditioning, however, were not sustainable as neuroprotection and neurological recovery were lost 28 days post-stroke. Although angioneurogenesis was not increased by post-conditioning, the favorable extracellular milieu facilitated intracerebral transplantation of neural progenitor cells 6 h post-stroke, resulting in persisted neuroprotection and neurological recovery. Thus, post-conditioning might support brain repair processes, but in view of its transient, neuroprotection is unlikely useful as stroke therapy in its current form.
authors.affiliation: Department of Neurology, University of Duisburg-Essen Medical School, Essen, Germany. thorsten.doeppner@uk-essen.de.|Regenerative and Restorative Medical Research Center, Istanbul Medipol University, Istanbul, Turkey. thorsten.doeppner@uk-essen.de.|Department of Neurology, University of Göttingen Medical School, Göttingen, Germany. thorsten.doeppner@uk-essen.de.
authors.forename: Thorsten R
authors.initials: TR
authors.lastname: Doeppner
authors.affiliation: Oberhavel Kliniken, Department of Internal Medicine, Oranienburg, Germany.
authors.forename: Maria
authors.initials: M
authors.lastname: Doehring
authors.affiliation: Department of Neurology, University of Duisburg-Essen Medical School, Essen, Germany.
authors.forename: Britta
authors.initials: B
authors.lastname: Kaltwasser
authors.affiliation: Sheffield Institute for Translational Neuroscience, University of Sheffield, Sheffield, UK.
authors.forename: Arshad
authors.initials: A
authors.lastname: Majid
authors.affiliation: Cancer Center, The First Affiliated Hospital, Jilin University, Changchun, Jilin, China.
authors.forename: Fengyan
authors.initials: F
authors.lastname: Lin
authors.affiliation: Department of Neurology, University of Göttingen Medical School, Göttingen, Germany.
authors.forename: Mathias
authors.initials: M
authors.lastname: Bähr
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 Medical School, Essen, Germany.
authors.forename: Dirk M
authors.initials: DM
authors.lastname: Hermann
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism; D004195:Disease Models, Animal; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism*; D057775:Ischemic Postconditioning; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000378:metabolism; D058953:Neural Stem Cells / Q000637:transplantation*; D000066829:Neuroprotection / Q000502:physiology*; D018384:Oxidative Stress / Q000502:physiology; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D020127:Recovery of Function; D033581:Stem Cell Transplantation; D020521:Stroke / Q000378:metabolism / Q000628:therapy*
chemical_list: D018840:HSP70 Heat-Shock Proteins; D016328:NF-kappa B; D020780:Matrix Metalloproteinase 9; C501830:Mmp9 protein, mouse; D046988:Proteasome Endopeptidase Complex
keywords: Cerebral ischemia; Hsp70; Neural progenitor cells; Post-conditioning; Preconditioning; Proteasome; Stroke; Transplantation