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

Nature Neuroscience volume 9, pages 487–488 (2006)Cite this article

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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.

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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).

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  • 10 April 2006

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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.

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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.).

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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

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  1. Annett Spudich
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  2. Ertugrul Kilic
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  3. Hongyi Xing
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  4. Ülkan Kilic
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  5. Katharina M Rentsch
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Correspondence to Dirk M Hermann.

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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)

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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

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