title: Glutamate-mediated upregulation of the multidrug resistance protein 2 in porcine and human brain capillaries.
abstract: As a member of the multidrug-resistance associated protein (MRP) family, MRP2 affects the brain entry of different endogenous and exogenous compounds. Considering the role of this transporter at the blood-brain barrier, the regulation is of particular interest. However, there is limited knowledge regarding the factors that regulate MRP2 in neurologic disease states. Thus, we addressed the hypothesis that MRP2 might be affected by a glutamate-induced signaling pathway that we previously identified as one key mechanism in the regulation of P-glycoprotein. Studies in isolated porcine brain capillaries confirmed that glutamate and N-methyl-d-aspartic acid (NMDA) exposure upregulates expression and function of MPR2. The involvement of the NMDA receptor was further suggested by the fact that the NMDA receptor antagonist MK-801 [(5S,10R)-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine], as well as the NMDA receptor glycine binding site antagonist L-701,324 [7-chloro-4-hydroxy-3-(3-phenoxy)phenyl-2(1H)-quinolinone], prevented the impact of glutamate. A role of cyclooxygenase-2 was indicated by coincubation with the cyclooxygenase-2 inhibitor celecoxib and the cyclooxygenase-1/-2 inhibitor indomethacin, which both efficaciously abolished a glutamate-induced upregulation of MRP2. Translational studies in human capillaries from surgical specimen demonstrated a relevant MRP2 efflux function and indicated an effect of glutamate exposure as well as its prevention by cyclooxygenase-2 inhibition. Taken together the findings provide first evidence for a role of a glutamate-induced NMDA receptor/cyclooxygenase-2 signaling pathway in the regulation of MRP2 expression and function. The response to excessive glutamate concentrations might contribute to overexpression of MRP2, which has been reported in neurologic diseases including epilepsy. The overexpression might have implications for brain access of various compounds including therapeutic drugs.
authors.affiliation: Institute of Pharmacology, Toxicology, and Pharmacy, Ludwig-Maximilians-University, Munich, Germany (H.L.M., J.D.S., H.P.); Neuropediatric Clinic and Clinic for Neurorehabilitation, Epilepsy Center for Children and Adolescents (B.P., T.P., T.G., G.K.) and Clinic for Neurosurgery and Epilepsy Surgery (M.K.), Schön Klinik Vogtareuth, Vogtareuth, Germany; and Paracelsus Medical University, Salzburg, Austria (G.K.).
authors.forename: Hiram
authors.initials: H
authors.lastname: Luna-Munguia
authors.affiliation: Institute of Pharmacology, Toxicology, and Pharmacy, Ludwig-Maximilians-University, Munich, Germany (H.L.M., J.D.S., H.P.); Neuropediatric Clinic and Clinic for Neurorehabilitation, Epilepsy Center for Children and Adolescents (B.P., T.P., T.G., G.K.) and Clinic for Neurosurgery and Epilepsy Surgery (M.K.), Schön Klinik Vogtareuth, Vogtareuth, Germany; and Paracelsus Medical University, Salzburg, Austria (G.K.).
authors.forename: Josephine D
authors.initials: JD
authors.lastname: Salvamoser
authors.affiliation: Institute of Pharmacology, Toxicology, and Pharmacy, Ludwig-Maximilians-University, Munich, Germany (H.L.M., J.D.S., H.P.); Neuropediatric Clinic and Clinic for Neurorehabilitation, Epilepsy Center for Children and Adolescents (B.P., T.P., T.G., G.K.) and Clinic for Neurosurgery and Epilepsy Surgery (M.K.), Schön Klinik Vogtareuth, Vogtareuth, Germany; and Paracelsus Medical University, Salzburg, Austria (G.K.).
authors.forename: Bettina
authors.initials: B
authors.lastname: Pascher
authors.affiliation: Institute of Pharmacology, Toxicology, and Pharmacy, Ludwig-Maximilians-University, Munich, Germany (H.L.M., J.D.S., H.P.); Neuropediatric Clinic and Clinic for Neurorehabilitation, Epilepsy Center for Children and Adolescents (B.P., T.P., T.G., G.K.) and Clinic for Neurosurgery and Epilepsy Surgery (M.K.), Schön Klinik Vogtareuth, Vogtareuth, Germany; and Paracelsus Medical University, Salzburg, Austria (G.K.).
authors.forename: Tom
authors.initials: T
authors.lastname: Pieper
authors.affiliation: Institute of Pharmacology, Toxicology, and Pharmacy, Ludwig-Maximilians-University, Munich, Germany (H.L.M., J.D.S., H.P.); Neuropediatric Clinic and Clinic for Neurorehabilitation, Epilepsy Center for Children and Adolescents (B.P., T.P., T.G., G.K.) and Clinic for Neurosurgery and Epilepsy Surgery (M.K.), Schön Klinik Vogtareuth, Vogtareuth, Germany; and Paracelsus Medical University, Salzburg, Austria (G.K.).
authors.forename: Thekla
authors.initials: T
authors.lastname: Getzinger
authors.affiliation: Institute of Pharmacology, Toxicology, and Pharmacy, Ludwig-Maximilians-University, Munich, Germany (H.L.M., J.D.S., H.P.); Neuropediatric Clinic and Clinic for Neurorehabilitation, Epilepsy Center for Children and Adolescents (B.P., T.P., T.G., G.K.) and Clinic for Neurosurgery and Epilepsy Surgery (M.K.), Schön Klinik Vogtareuth, Vogtareuth, Germany; and Paracelsus Medical University, Salzburg, Austria (G.K.).
authors.forename: Manfred
authors.initials: M
authors.lastname: Kudernatsch
authors.affiliation: Institute of Pharmacology, Toxicology, and Pharmacy, Ludwig-Maximilians-University, Munich, Germany (H.L.M., J.D.S., H.P.); Neuropediatric Clinic and Clinic for Neurorehabilitation, Epilepsy Center for Children and Adolescents (B.P., T.P., T.G., G.K.) and Clinic for Neurosurgery and Epilepsy Surgery (M.K.), Schön Klinik Vogtareuth, Vogtareuth, Germany; and Paracelsus Medical University, Salzburg, Austria (G.K.).
authors.forename: Gerhard
authors.initials: G
authors.lastname: Kluger
authors.affiliation: Institute of Pharmacology, Toxicology, and Pharmacy, Ludwig-Maximilians-University, Munich, Germany (H.L.M., J.D.S., H.P.); Neuropediatric Clinic and Clinic for Neurorehabilitation, Epilepsy Center for Children and Adolescents (B.P., T.P., T.G., G.K.) and Clinic for Neurosurgery and Epilepsy Surgery (M.K.), Schön Klinik Vogtareuth, Vogtareuth, Germany; and Paracelsus Medical University, Salzburg, Austria (G.K.) potschka@pharmtox.vetmed.uni-muenchen.de.
authors.forename: Heidrun
authors.initials: H
authors.lastname: Potschka
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000096:biosynthesis*; D000293:Adolescent; D000818:Animals; D001692:Biological Transport; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000378:metabolism; D001921:Brain / Q000098:blood supply* / Q000187:drug effects / Q000378:metabolism; D002196:Capillaries / Q000187:drug effects / Q000378:metabolism*; D002648:Child; D002675:Child, Preschool; D051546:Cyclooxygenase 2 / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004827:Epilepsy / Q000378:metabolism; D005260:Female; D018698:Glutamic Acid / Q000494:pharmacology*; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D013552:Swine; D015854:Up-Regulation; D000097202:ATP-Binding Cassette Sub-Family B Member 4
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D051546:Cyclooxygenase 2; D018698:Glutamic Acid; D016194:Receptors, N-Methyl-D-Aspartate; D000097202:ATP-Binding Cassette Sub-Family B Member 4