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Molecular Neurobiology

, Volume 53, Issue 9, pp 6332–6341 | Cite as

Systemic Proteasome Inhibition Induces Sustained Post-stroke Neurological Recovery and Neuroprotection via Mechanisms Involving Reversal of Peripheral Immunosuppression and Preservation of Blood–Brain–Barrier Integrity

  • Thorsten R. Doeppner
  • Britta Kaltwasser
  • Ulrike Kuckelkorn
  • Petra Henkelein
  • Eva Bretschneider
  • Ertugrul Kilic
  • Dirk M. Hermann
Article

Abstract

In view of its profound effect on cell survival and function, the modulation of the ubiquitin-proteasome-system has recently been shown to promote neurological recovery and brain remodeling after focal cerebral ischemia. Hitherto, local intracerebral delivery strategies were used, which can hardly be translated to human patients. We herein analyzed effects of systemic intraperitoneal delivery of the proteasome inhibitor BSc2118 on neurological recovery, brain injury, peripheral and cerebral immune responses, neurovascular integrity, as well as cerebral neurogenesis and angiogenesis in a mouse model of transient intraluminal middle cerebral artery occlusion. Systemic delivery of BSc2118 induced acute neuroprotection reflected by reduced infarct volume when delivered up to 9 h post-stroke. The latter was associated with reduced brain edema and stabilization of blood–brain–barrier integrity, albeit cerebral proteasome activity was only mildly reduced. Neuronal survival persisted in the post-acute stroke phase up to 28 days post-stroke and was associated with improved neurological recovery when the proteasome inhibitor was continuously delivered over 7 days. Systemic proteasome inhibition prevented stroke-induced acute leukocytosis in peripheral blood and reversed the subsequent immunosuppression, namely, the reduction of blood lymphocyte and granulocyte counts. On the contrary, post-ischemic brain inflammation, cerebral HIF-1α abundance, cell proliferation, neurogenesis, and angiogenesis were not influenced by the proteasome inhibitor. The modulation of peripheral immune responses might thus represent an attractive target for the clinical translation of proteasome inhibitors.

Keywords

Cerebral ischemia Stroke Proteasome Neuroprotection Neuroregeneration Inflammation 

Notes

Acknowledgments

This study was supported by grants from the German Research Council (DFG, No. HE3173/2-2 and No. HE3173/3-1 to DMH) and a grant from the Scientific and Technological Research Council of Turkey (TUBITAK, No. 2221 to TRD).

Compliance with Ethical Standards

All studies were performed according to local government authorities.

Conflict of Interest

The authors declare that they have no competing interests.

Supplementary material

12035_2015_9533_MOESM1_ESM.pdf (36 kb)
ESM 1 (PDF 35 kb)

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Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  • Thorsten R. Doeppner
    • 1
    • 2
  • Britta Kaltwasser
    • 1
  • Ulrike Kuckelkorn
    • 3
  • Petra Henkelein
    • 3
  • Eva Bretschneider
    • 4
  • Ertugrul Kilic
    • 2
  • Dirk M. Hermann
    • 1
  1. 1.Department of NeurologyUniversity of Duisburg-EssenEssenGermany
  2. 2.Regenerative and Restorative Medical Research CenterIstanbul Medipol UniversityIstanbulTurkey
  3. 3.Department of BiochemistryCharité-UniversitätsmedizinBerlinGermany
  4. 4.Department of OtorhinolaryngologyJohannes Wesling KlinikumMindenGermany

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