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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10 April 2006
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Notes
*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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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)
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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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DOI: https://doi.org/10.1038/nn1676
