title: Glutamate-Mediated Down-Regulation of the Multidrug-Resistance Protein BCRP/ABCG2 in Porcine and Human Brain Capillaries.
abstract: Breast cancer resistance protein (BCRP) functions as a major molecular gatekeeper at the blood-brain barrier. Considering its impact on access to the brain by therapeutic drugs and harmful xenobiotics, it is of particular interest to elucidate the mechanisms of its regulation. Excessive glutamate concentrations have been reported during epileptic seizures or as a consequence of different brain insults including brain ischemia. Previously, we have demonstrated that glutamate can trigger an induction of the transporter P-glycoprotein. These findings raised the question whether other efflux transporters are affected in a comparable manner. Glutamate exposure proved to down-regulate BCRP transport function and expression in isolated porcine capillaries. The reduction was efficaciously prevented by coincubation with N-methyl-d-aspartate (NMDA) receptor antagonist MK-801. The involvement of the NMDA receptor in the down-regulation of BCRP was further confirmed by experiments showing an effect of NMDA exposure on brain capillary BCRP transport function and expression. Pharmacological targeting of cyclooxygenase-1 and -2 (COX-1 and -2) using the nonselective inhibitor indomethacin, COX-1 inhibitor SC-560, and COX-2 inhibitor celecoxib revealed a contribution of COX-2 activity to the NMDA receptor's downstream signaling events affecting BCRP. Translational studies were performed using human capillaries isolated from surgical specimens of epilepsy patients. The findings confirmed a glutamate-induced down-regulation of BCRP transport activity in human capillaries, which argued against major species differences. In conclusion, our data reveal a novel mechanism of BCRP down-regulation in porcine and human brain capillaries. Moreover, together with previous data sets for P-glycoprotein, the findings point to a contrasting impact of the signaling pathway on the regulation of BCRP and P-glycoprotein. The effect of glutamate and arachidonic acid signaling on BCRP function might have implications for brain drug delivery and for radiotracer brain access in epilepsy patients and patients with other brain insults.
authors.affiliation: †Institute of Pharmacology, Toxicology, and Pharmacy, Ludwig-Maximilians-University, Koeniginstrasse 16, D-80539 Munich, Germany.
authors.forename: Josephine D
authors.initials: JD
authors.lastname: Salvamoser
authors.affiliation: †Institute of Pharmacology, Toxicology, and Pharmacy, Ludwig-Maximilians-University, Koeniginstrasse 16, D-80539 Munich, Germany.
authors.forename: Janine
authors.initials: J
authors.lastname: Avemary
authors.affiliation: †Institute of Pharmacology, Toxicology, and Pharmacy, Ludwig-Maximilians-University, Koeniginstrasse 16, D-80539 Munich, Germany.
authors.forename: Hiram
authors.initials: H
authors.lastname: Luna-Munguia
authors.forename: Bettina
authors.initials: B
authors.lastname: Pascher
authors.forename: Thekla
authors.initials: T
authors.lastname: Getzinger
authors.forename: Tom
authors.initials: T
authors.lastname: Pieper
authors.forename: Manfred
authors.initials: M
authors.lastname: Kudernatsch
authors.affiliation: ∥Paracelsus Medical University, 5020 Salzburg, Austria.
authors.forename: Gerhard
authors.initials: G
authors.lastname: Kluger
authors.affiliation: †Institute of Pharmacology, Toxicology, and Pharmacy, Ludwig-Maximilians-University, Koeniginstrasse 16, D-80539 Munich, Germany.
authors.forename: Heidrun
authors.initials: H
authors.lastname: Potschka
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000378:metabolism*; D002196:Capillaries / Q000378:metabolism*; D005260:Female; D051272:Glucose Transporter Type 1 / Q000378:metabolism*; D018698:Glutamic Acid / Q000378:metabolism*; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D013552:Swine
chemical_list: D018528:ATP-Binding Cassette Transporters; D051272:Glucose Transporter Type 1; D018698:Glutamic Acid
keywords: ABCG2; NMDA receptor; blood−brain barrier; breast cancer resistance protein; drug resistance; glutamate; multidrug transporter