Doeppner, T.R., Doehring, M., Kaltwasser, B. et al. (5 more authors) (2017) Ischemic Post-Conditioning Induces Post-Stroke Neuroprotection via Hsp70-Mediated Proteasome Inhibition and Facilitates Neural Progenitor Cell Transplantation. Molecular Neurobiology, 54 (8). pp. 6061-6073. ISSN 0893-7648
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.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © 2016 Humana Press |
Keywords: | Cerebral ischemia; Hsp70; Neural progenitor cells; Post-conditioning; Preconditioning; Proteasome; Stroke; Transplantation |
Dates: |
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Institution: | The University of Sheffield |
Academic Units: | The University of Sheffield > Faculty of Medicine, Dentistry and Health (Sheffield) > Department of Neuroscience (Sheffield) The University of Sheffield > Sheffield Teaching Hospitals |
Depositing User: | Symplectic Sheffield |
Date Deposited: | 14 Dec 2016 10:23 |
Last Modified: | 14 Nov 2017 11:56 |
Published Version: | http://doi.org/10.1007/s12035-016-0137-3 |
Status: | Published |
Publisher: | Springer US |
Refereed: | Yes |
Identification Number: | 10.1007/s12035-016-0137-3 |
Related URLs: | |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:109293 |