ABCC1: a gateway for drugs to the ischaemic brain

ATP-binding cassette (ABC) transporters are ATP-dependent flippases located at the blood brain barrier (BBB) that are involved in the elimination of drugs from the brain. While the majority of transporters are expressed on the luminal surface of the endothelium, carrying drugs from the brain back into the blood against concentration gradients1, some transporters, including ABCC1 (previously multidrug resistance-associated protein-1), predominantly exhibit abluminal localization on vascular endothelium. Until now, the function of these abluminal transporters remained largely unclear. To elucidate the implication of ABCC1 for the pharmacotherapy of ischemic stroke, we submitted adult mice to 30 and 90min of middle cerebral artery (MCA) occlusion1. Immunohistochemical studies and Western blots using enriched capillary fractions showed that ABCC1 expression was decreased in ischemic brain at 3–24h after reperfusion onset. Deactivation studies, in which the pharmacological ABCC1 inhibitor MK571 was delivered in ischemic mice showed that brain levels of the ABCC1 substrates estradiol-17β-D-glucuronide (17bβEG) and S-nitrosoglutathione (GSNO) decreased in ischemic brain tissue by more than 100-fold, indicating that brain accumulation of both drugs requires the functionality of ABCC1. In animals submitted to stroke, the delivery of both ABCC1 substrates resulted in a dose-dependent decrease (17βEG) or increase (GSNO) in ischemic injury, which was reversed upon pharmacological (MK571) or genetic (abcc1-/-) deactivation. Our data suggest that ABCC1 serves as gateway for drugs into the stroke brain. We predict that the selection of drugs acting as substrates of abluminal, but not luminal ABC transporters may greatly facilitate pharmacological therapies in brain diseases.