ABCC1: a gateway for pharmacological compounds to the ischaemic brain.
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.
Kilic
Ertugrul
E
Department of Neurology, University Hospital Zurich, Zurich, Switzerland.
Spudich
Annett
A
Kilic
Ulkan
U
Rentsch
Katharina M
KM
Vig
Raluca
R
Matter
Christian M
CM
Wunderli-Allenspach
Heidi
H
Fritschy
Jean-Marc
JM
Bassetti
Claudio L
CL
Hermann
Dirk M
DM
D000818:Animals; D001692:Biological Transport; D001812:Blood-Brain Barrier / Q000502:physiology*; D015153:Blotting, Western / Q000379:methods; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D002545:Brain Ischemia / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D002853:Chromatography, Liquid; D004337:Drug Carriers; D004958:Estradiol / Q000031:analogs & derivatives / Q000032:analysis / Q000378:metabolism; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D023421:Models, Animal; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D011422:Propionates / Q000494:pharmacology; D011804:Quinolines / Q000494:pharmacology; D026422:S-Nitrosoglutathione / Q000032:analysis / Q000378:metabolism; D013057:Spectrum Analysis; D013154:Spleen / Q000378:metabolism; D013737:Testis / Q000378:metabolism
D004337:Drug Carriers; D004958:Estradiol; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D011422:Propionates; D011804:Quinolines; D026422:S-Nitrosoglutathione; C025483:estradiol-17 beta-glucuronide; C059141:verlukast; C421109:multidrug resistance-associated protein 1