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Brain Advance Access published online on September 16, 2008
Brain, doi:10.1093/brain/awn222
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© The Author (2008). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

ABCC1: a gateway for pharmacological compounds to the ischaemic brain

Ertugrul Kilic1, Annett Spudich1, Ülkan Kilic1, Katharina M. Rentsch2, Raluca Vig1, Christian M. Matter3, Heidi Wunderli-Allenspach4, Jean-Marc Fritschy5, Claudio L. Bassetti1 and Dirk M. Hermann1

1Department of Neurology, 2Department of Clinical Chemistry, 3Department of Cardiology, University Hospital Zurich, Frauenklinikstr. 26, CH-8091 Zurich, 4Institute of Pharmaceutical Sciences, Swiss Federal Institute of Technology, Wolfgang-Pauli-Str. 10, CH-8093 Zurich and 5Institute of Pharmacology and Toxicology, University of Zurich, Winterthurer Str. 190, CH-8057 Zurich, Switzerland

Correspondence to: Prof. Dr. Dirk M. Hermann, Department of Neurology, University of Duisburg-Essen, Hufelandstr. 55, D-45122 Essen, Germany E-mail: dirk.hermann{at}uk-essen.de

By preventing access of drugs to the CNS, the blood–brain barrier hampers developments in brain pharmacotherapy. Strong efforts are currently being made to identify drugs that accumulate more efficaciously in ischaemic brain tissue. We identified an ATP-binding cassette (ABC) transporter, ABCC1, which is expressed on the abluminal surface of the brain capillary endothelium and mildly downregulated in response to focal cerebral ischaemia, induced by intraluminal middle cerebral artery occlusion. In biodistribution studies we show that ABCC1 promotes the accumulation of known neuroprotective and neurotoxic compounds in the ischaemic and non-ischaemic brain, ABCC1 deactivation reducing tissue concentrations by up to two orders of magnitude. As such, ABCC1's expression and functionality in the brain differs from the liver, spleen and testis, where ABCC1 is strongly expressed on parenchymal cells, resulting—in case of liver and testis—in directed transport from the tissue into the blood. After focal cerebral ischaemia, ABCC1 deactivation abolished the efficacy of both neuroprotective and neurotoxic compounds. Our data indicate that ABCC1 acts as gateway for pharmacological compounds to the stroke brain. We suggest that the tailoring of compounds binding to abluminal but not luminal ABC transporters may facilitate stroke pharmacotherapy.

Key Words: ABC transporter; blood–brain barrier; neuroprotection; pharmacotherapy; stroke

Abbreviations: ABC, ATP-binding cassette; BBB, blood–brain barrier; LC-MS, liquid chromatography/mass spectrometry; LDF, laser Doppler flow; MCA, middle cerebral artery; Mdr, multi-drug resistance transporter; Mrp, multi-drug resistance-associated protein; TUNEL, terminal transferase biotinylated-dUTP nick end labelling

Received February 12, 2008. Revised August 11, 2008. Accepted August 22, 2008.


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