Skip to main content
SpringerLink
Log in

Inhibition of multidrug resistance transporter-1 facilitates neuroprotective therapies after focal cerebral ischemia

  • Brief Communication
  • Published:

From Nature Neuroscience

View current issue Submit your manuscript

This article has been updated

Abstract

The blood-brain barrier possesses active transporters carrying brain-permeable xenobiotics back into the blood against concentration gradients. We demonstrate that multidrug resistance transporter (Mdr)-1 is upregulated on capillary endothelium after focal cerebral ischemia; moreover, Mdr-1 deactivation by pharmacological inhibition or genetic knockout preferably enhances the accumulation and efficacy of two neuroprotectants known as Mdr-1 substrates in the ischemic brain. We predict that Mdr-1 inhibition may greatly facilitate neuroprotective therapies.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Figure 1: Mdr-1 is upregulated on capillary endothelium after focal cerebral ischemia.
Figure 2: Mdr-1 deactivation by pharmacological inhibition with TQD or Abcb1a-Abcb1b knockout (Abcb1a-Abcb1b−/−) potentiates the neuroprotective efficacy of FK506 and rifampicin (Rif).

Similar content being viewed by others

Change history

  • 10 April 2006

    Figure replaced

Notes

  1. *Note: In the HTML version of this article originally published online, the layout of Figure 2 obscured the relationship between the key and the figure panels. The error has been corrected in the HTML version of the article.

References

  1. Löscher, W. & Potschka, H. Nat. Rev. Neurosci. 6, 591–602 (2005).

    Article  Google Scholar 

  2. Gottesman, M.M., Fojo, T. & Bates, S.E. Nat. Rev. Cancer 2, 48–58 (2002).

    Article  CAS  Google Scholar 

  3. Wartenberg, M. et al. FASEB J. 17, 503–505 (2003).

    Article  CAS  Google Scholar 

  4. Comerford, K.M. et al. Cancer Res. 62, 3387–3394 (2002).

    CAS  PubMed  Google Scholar 

  5. Wang, Y. et al. Brain 128, 52–63 (2005).

    Article  Google Scholar 

  6. Sharkey, J. & Butcher, S.P. Nature 371, 336–339 (1994).

    Article  CAS  Google Scholar 

  7. Yulug, B., Kilic, Ü., Kilic, E. & Bähr, M. Brain Res. 996, 76–80 (2004).

    Article  CAS  Google Scholar 

  8. Fisher, M. et al. Stroke therapy academic industry roundtable IV. Stroke 36, 1808–1913 (2005).

    Article  Google Scholar 

  9. Sisodiya, S.M., Lin, W.-R., Squier, M.V. & Thom, M. Lancet 357, 42–43 (2001).

    Article  CAS  Google Scholar 

  10. Potschka, H. & Löscher, W. J. Pharmacol. Exp. Ther. 301, 7–14 (2002).

    Article  Google Scholar 

  11. Synold, T.W., Dussault, I. & Forman, B.M. Nat. Med. 7, 584–590 (2001).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank A. Fendel and M. Günthert for technical assistance and S. Krämer for stimulating discussions. This research was supported by the National Center of Competence in Research 'Neural plasticity and repair', Center of Integrative Human Physiology (CIHP), Swiss National Science Foundation (3200B0-100790/1), Baasch-Medicus Foundation and Hermann Klaus Foundation (to D.M.H.).

Author information

Authors and Affiliations

  1. Department of Neurology, University Hospital Zurich, Frauenklinikstr. 26, Zurich, CH-8091, Switzerland

    Annett Spudich, Ertugrul Kilic, Hongyi Xing, Ülkan Kilic, Claudio L Bassetti & Dirk M Hermann

  2. Department of Clinical Chemistry, University Hospital Zurich, Rämistr. 100, Zurich, CH-8091, Switzerland

    Katharina M Rentsch

  3. Institute of Pharmaceutical Sciences, Swiss Federal Institute of Technology, Wolfgang-Pauli-Str. 10, Zurich, CH-8093, Switzerland

    Heidi Wunderli-Allenspach

Authors
  1. Annett Spudich
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ertugrul Kilic
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Hongyi Xing
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ülkan Kilic
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Katharina M Rentsch
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Heidi Wunderli-Allenspach
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Claudio L Bassetti
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Dirk M Hermann
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Dirk M Hermann.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Fig. 1

Mdr-1 expression is increased in the ischemic brain. (PDF 172 kb)

Supplementary Fig. 2

The Mdr-1 inhibitor TQD preferably increases brain concentrations of FK506 and rifampicin in the ischemic brain. (PDF 30 kb)

Supplementary Fig. 3

Regimen of TQD, FK506 and rifampicin (Rif) delivery used in order to study the role of the Mdr-1 transporter in post-ischemic neuroprotection. (PDF 24 kb)

Supplementary Methods (PDF 101 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Spudich, A., Kilic, E., Xing, H. et al. Inhibition of multidrug resistance transporter-1 facilitates neuroprotective therapies after focal cerebral ischemia. Nat Neurosci 9, 487–488 (2006). https://doi.org/10.1038/nn1676

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nn1676

  • Springer Nature America, Inc.

This article is cited by

Search

Navigation