Ischemic post-conditioning induces post-stroke neuroprotection via Hsp70-mediated proteasome inhibition and facilitates neural progenitor cell transplantation
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2017Author
Doeppner, Thorsten R.Doehring, Maria
Kaltwasser, Britta
Majid, Arshad
Lin, Fengyan
Bahr, Mathias
Kılıç, Ertuğrul
Hermann, Dirk M.
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Doeppner, T. R., Doehring, M., Kaltwasser, B., Majid, A., Lin, F., Bahr, M. ... Hermann, D. M. (2017). Ischemic post-conditioning induces post-stroke neuroprotection via Hsp70-mediated proteasome inhibition and facilitates neural progenitor cell transplantation. Molecular Neurobiology, 54(8), 6061-6073. https://dx.doi.org/10.1007/s12035-016-0137-3Abstract
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 poststroke, 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)-kappa B 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.