Inhibition of multidrug resistance transporter-1 facilitates neuroprotective therapies after focal cerebral ischemia.
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.
Spudich
Annett
A
Department of Neurology, University Hospital Zurich, Frauenklinikstr. 26, CH-8091 Zurich, Switzerland.
Kilic
Ertugrul
E
Xing
Hongyi
H
Kilic
Ulkan
U
Rentsch
Katharina M
KM
Wunderli-Allenspach
Heidi
H
Bassetti
Claudio L
CL
Hermann
Dirk M
DM
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001812:Blood-Brain Barrier / Q000502:physiology; D001921:Brain / Q000033:anatomy & histology / Q000502:physiology; D002545:Brain Ischemia / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D002196:Capillaries / Q000166:cytology / Q000378:metabolism; D002560:Cerebrovascular Circulation / Q000502:physiology; D004730:Endothelium, Vascular / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000378:metabolism; D007166:Immunosuppressive Agents / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D011804:Quinolines / Q000378:metabolism*; D012293:Rifampin / Q000378:metabolism; D016559:Tacrolimus / Q000378:metabolism
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D004791:Enzyme Inhibitors; D007166:Immunosuppressive Agents; D018696:Neuroprotective Agents; D011804:Quinolines; C402343:tariquidar; D012293:Rifampin; D016559:Tacrolimus