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: Thorsten R Doeppner, Britta Kaltwasser, Jin Fengyan, Dirk M Hermann, Mathias Bähr
• Journal: Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism (J Cereb Blood Flow Metab) Vol. 33 Issue 11 Pg. 1778-88 (Nov 2013) ISSN: 1559-7016 [Electronic] United States
• PMID: 23881248 (Publication Type: Journal Article)

Chemical References

• Anti-Inflammatory Agents
• HSP70 Heat-Shock Proteins
• Neuroprotective Agents
• Recombinant Fusion Proteins
• tat Gene Products, Human Immunodeficiency Virus

Topics

• Animals
• Anti-Inflammatory Agents (administration & dosage, pharmacology, therapeutic use)
• HSP70 Heat-Shock Proteins (administration & dosage, genetics, pharmacology, therapeutic use)
• Ischemic Attack, Transient (drug therapy, immunology, pathology, therapy)
• Male
• Mice
• Mice, Inbred C57BL
• Microglia (drug effects, immunology, pathology)
• Neural Stem Cells (transplantation)
• Neuroprotective Agents (administration & dosage, pharmacology, therapeutic use)
• Recombinant Fusion Proteins (administration & dosage, genetics, pharmacology, therapeutic use)
• Stem Cell Transplantation
• Stroke (drug therapy, immunology, pathology, therapy)
• tat Gene Products, Human Immunodeficiency Virus (genetics)