title: TAT-Hsp70 induces neuroprotection against stroke via anti-inflammatory actions providing appropriate cellular microenvironment for transplantation of neural precursor cells.
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-κB) as well as proteasomal degradation of the NF-κB regulator Ikappa B alpha (IκB-α) 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.
authors.affiliation: 1] Department of Neurology, University of Duisburg-Essen Medical School, Essen, Germany [2] Department of Neurology, University of Goettingen Medical School, Goettingen, Germany.
authors.forename: Thorsten R
authors.initials: TR
authors.lastname: Doeppner
authors.forename: Britta
authors.initials: B
authors.lastname: Kaltwasser
authors.forename: Jin
authors.initials: J
authors.lastname: Fengyan
authors.forename: Dirk M
authors.initials: DM
authors.lastname: Hermann
authors.forename: Mathias
authors.initials: M
authors.lastname: Bähr
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D018840:HSP70 Heat-Shock Proteins / Q000008:administration & dosage / Q000235:genetics / Q000494:pharmacology / Q000627:therapeutic use*; D002546:Ischemic Attack, Transient / Q000188:drug therapy / Q000276:immunology / Q000473:pathology / Q000628:therapy; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D058953:Neural Stem Cells / Q000637:transplantation*; D018696:Neuroprotective Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage / Q000235:genetics / Q000494:pharmacology / Q000627:therapeutic use; D033581:Stem Cell Transplantation; D020521:Stroke / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology / Q000628:therapy; D054322:tat Gene Products, Human Immunodeficiency Virus / Q000235:genetics*
chemical_list: D000893:Anti-Inflammatory Agents; D018840:HSP70 Heat-Shock Proteins; D018696:Neuroprotective Agents; D011993:Recombinant Fusion Proteins; D054322:tat Gene Products, Human Immunodeficiency Virus