TAT-Hsp70 induces neuroprotection against stroke via anti-inflammatory actions providing appropriate cellular microenvironment for transplantation of neural precursor cells

2013 | journal article; research paper. A publication with affiliation to the University of Göttingen.

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​TAT-Hsp70 induces neuroprotection against stroke via anti-inflammatory actions providing appropriate cellular microenvironment for transplantation of neural precursor cells​
Doeppner, T. R. ; Kaltwasser, B.; Jin Fengyan, J. F.; Hermann, D. M. & Bähr, M. ​ (2013) 
Journal of Cerebral Blood Flow & Metabolism33(11) pp. 1778​-1788​.​ DOI: https://doi.org/10.1038/jcbfm.2013.126 

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Authors
Doeppner, T. R. ; Kaltwasser, B.; Jin Fengyan, J. F.; Hermann, D. M.; Bähr, M. 
Abstract
Heat-shock protein 70 (Hsp70) protects against cerebral ischemia, which is attributed to its chaperone activity. However, recent reports also describe pro-inflammatory actions of Hsp70 via activation of Toll-like receptors (TLR). Using membrane-permeable transactivator of transcription (TAT)-Hsp70, we analyzed TAT-Hsp70-induced neuroprotection and its underlying mechanism after cerebral ischemia in mice. Infusion of TAT-Hsp70 reduced infarct volume and enhanced blood-brain barrier integrity on day 3 poststroke, when given no later than 12 hours. The latter was associated with reduction of microglial activation, although upregulation of pro-inflammatory TLR-2/4 was observed both in verum and in control animals. Nevertheless, protein abundance and nuclear translocation of downstream nuclear factor kappa B (NF-kappa B) as well as proteasomal degradation of the NF-kappa B regulator Ikappa B alpha (I kappa B-alpha) were significantly reduced by TAT-Hsp70. TAT-Hsp70-induced neuroprotection and functional recovery were restricted to 4 weeks only. However, TAT-Hsp70 provided an appropriate extracellular milieu for delayed intravenous transplantation of adult neural precursor cells (NPCs). Thus, NPCs that were grafted 28 days poststroke induced long-term neuroprotection for at least 3 months, which was not due to integration of grafted cells but rather due to paracrine effects of transplanted NPCs. Conclusively, TAT-Hsp70 ameliorates postischemic inflammation via proteasome inhibition, thus providing an appropriate extracellular milieu for delayed NPC transplantation and culminating in long-term neuroprotection.
Issue Date
2013
Journal
Journal of Cerebral Blood Flow & Metabolism 
ISSN
0271-678X
eISSN
1559-7016
Language
English

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