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 10min after reperfusion onset. Animals were sacrificed 24h or 28days post-stroke. Post-conditioning reduced infarct volume and neurological deficits 24h 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 28days post-stroke. Although angioneurogenesis was not increased by post-conditioning, the favorable extracellular milieu facilitated intracerebral transplantation of neural progenitor cells 6h 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.
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