Purpose and methods: The blood-brain barrier possesses transporters on its luminal surface, which carry
back xenobiotics into the vasculature against concentration gradients. To define the
role of one of them, multidrug resistance transporter (Mdr)-1, which is physiologically
expressed in the brain and made responsible for pharmacoresistance in epilepsy, we
subjected mice to middle cerebral artery occlusions.
Results: In histochemical studies we show that Mdr-1 is upregulated on endothelial cells after
ischemia. Following Mdr-1 deactivation by its pharmacological inhibitor, tariquidar,
tissue concentrations of the neuroprotectant and known Mdr-1 substrate FK506 were
selectively increased in the ischemic brain by ˜14-fold. Inhibition of Mdr-1 by tariquidar
or mdr-1(a/b)-knockout potentiated the neuroprotective activity of two Mdr-1 substrates
(FK506, rifampicin), providing tissue rescue at doses otherwise subtherapeutic.
Conclusions: Our results demonstrate the in vivo relevance of Mdr-1 after stroke. As up to 50%
of pharmaceutical compounds newly developed are thought to be Mdr-1 substrates, we
predict that Mdr-1 inhibition may greatly facilitate stroke therapies.
