Glutamate-Mediated Upregulation of the Multidrug Resistance Protein 2 in Porcine and Human Brain Capillaries

Luna-Munguía, Hiram; Salvamoser, Josephine D.; Pascher, B; Pieper, Tom; Getzinger, Thekla; Kudernatsch, Manfred; Kluger, Gerhard; Potschka, Heidrun

doi:10.1124/jpet.114.218180

Cited by 23 publications

(19 citation statements)

References 52 publications

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“…112,116 This may be due to low basal expression of Mrp2, which may be upregulated in response to cellular stressors such as oxidative stress. 117,118 In mice, there are notable differences in Mrp expression between strains and between vessels of different diameters. For example, Friend virus B (FVB) mice appear to lack Mrp2 in brain vessels, but it is present in C57BL/6 and Swiss mice.…”

Section: Bbb Protection In Ischemic Strokementioning

confidence: 99%

Role of Transporters in Central Nervous System Drug Delivery and Blood-Brain Barrier Protection: Relevance to Treatment of Stroke

Brzica

Abdullahi

Ibbotson

et al. 2017

J Cent Nerv Syst Dis

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Ischemic stroke is a leading cause of morbidity and mortality in the United States. The only approved pharmacologic treatment for ischemic stroke is thrombolysis via recombinant tissue plasminogen activator (r-tPA). A short therapeutic window and serious adverse events (ie, hemorrhage, excitotoxicity) greatly limit r-tPA therapy, which indicates an essential need to develop novel stroke treatment paradigms. Transporters expressed at the blood-brain barrier (BBB) provide a significant opportunity to advance stroke therapy via central nervous system delivery of drugs that have neuroprotective properties. Examples of such transporters include organic anion–transporting polypeptides (Oatps) and organic cation transporters (Octs). In addition, multidrug resistance proteins (Mrps) are transporter targets in brain microvascular endothelial cells that can be exploited to preserve BBB integrity in the setting of stroke. Here, we review current knowledge on stroke pharmacotherapy and demonstrate how endogenous BBB transporters can be targeted for improvement of ischemic stroke treatment.

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Section: Bbb Protection In Ischemic Strokementioning

confidence: 99%

Role of Transporters in Central Nervous System Drug Delivery and Blood-Brain Barrier Protection: Relevance to Treatment of Stroke

Brzica

Abdullahi

Ibbotson

et al. 2017

J Cent Nerv Syst Dis

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“…In similar study, the same group showed that MRP2 expression and activity increased significantly in porcine and human BBB models after exposure to glutamate. The NMDA/COX-2 cascade was shown to be involved (Luna-Munguia et al, 2015). …”

Section: Introductionmentioning

confidence: 99%

Regulation of ABC efflux transporters at blood-brain barrier in health and neurological disorders

et al. 2015

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The strength of the blood-brain barrier (BBB) in providing protection to the central nervous system from exposure to circulating chemicals is maintained by tight junctions between endothelial cells and by a broad range of transporter proteins that regulate exchange between CNS and blood. The most important transporters that restrict the permeability of large number of toxins as well as therapeutic agents are the ABC transporters. Among them, P-gp, BCRP, MRP1 and MRP2 are the utmost studied. These efflux transporters are neuroprotective, limiting the brain entry of neurotoxins; however, they could also restrict the entry of many therapeutics and contribute to CNS pharmacoresistance. Characterization of several regulatory pathways that govern expression and activity of ABC efflux transporters in the endothelium of brain capillaries have led to an emerging consensus that these processes are complex and contain several cellular and molecular elements. Alterations in ABC efflux transporters expression and/or activity occur in several neurological diseases. Here, we review the signaling pathways that regulate expression and transport activity of P-gp, BCRP, MRP1 and MRP2 as well as how their expression/activity changes in neurological diseases.

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“…For OAT and P-gp an apical and sub-apical localization was stated, whereas MRP1 was demonstrated to be expressed at the basolateral membrane. 36,37 Indomethacin as substrate for OAT2 and the MRP family, 22,23 valspodar representing a P-gp inhibitor 38 and fumitremorgin C as ABCG2 inhibitor 39 did not inhibit the efflux of organic mercury compounds out of the brain. In the rat choroid plexus, LAT1 has been demonstrated to be localized at the basolateral membrane 29,30 and thus further studies could prove whether LAT1 is also localized on the basolateral membrane of the applied primary porcine blood-CSF barrier model and might contribute to the observed efflux of the organic mercury compounds in the present study.…”

Section: Discussionmentioning

confidence: 99%

“…Fumitremorgin C (498% purity) was used to inhibit the ATP binding cassette (ABC)-transporter G2 (ABCG2), PSC 833 (valspodar, 498% purity) to inhibit P-glycoprotein (P-gp/ABCB1) and indomethacin (499% purity, all Sigma Aldrich) to inhibit organic anion transporter 2 (OAT2) and/or multidrug resistance associated protein (MRP), respectively. [21][22][23] The stock solutions of the respective inhibitors were prepared in dimethyl sulfoxide (DMSO, Roth, Karlsruhe, Germany) and applied in the apical as well as in the basolateral compartment simultaneously with a final inhibitor concentration of 10 mM 1 h before treatment with the mercury compounds on both sides (1 mM). The DMSO concentration did not exceed a concentration of 1% in the wells.…”

Section: Cytotoxicity Testingmentioning

confidence: 99%

Blood-Cerebrospinal Fluid Barrier

Gibbs¹,

Thomas²

2015

Encyclopedia of Psychopharmacology

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U n i v e r s i t ä t P o t s d a mPostprints der Universität Potsdam Mathematisch-Naturwissenschaftliche Reihe ; 200 1420 | Metallomics, 2015 , 7, 1420 --1430 This journal is © The Royal Society of Chemistry 2015Cite this: Metallomics, 2015, 7, 1420The blood-cerebrospinal fluid barrier -first evidence for an active transport of organic mercury compounds out of the brain Hanna Lohren, a Julia Bornhorst, a Hans-Joachim Galla b and Tanja Schwerdtle* a Exposure to organic mercury compounds promotes primarily neurological effects. Although methylmercury is recognized as a potent neurotoxicant, its transfer into the central nervous system (CNS) is not fully evaluated.While methylmercury and thiomersal pass the blood-brain barrier, limited data are available regarding the second brain regulating interface, the blood-cerebrospinal fluid (CSF) barrier. This novel study was designed to investigate the effects of organic as well as inorganic mercury compounds on, and their transfer across, a porcine in vitro model of the blood-CSF barrier for the first time. The barrier system is significantly more sensitive towards organic Hg compounds as compared to inorganic compounds regarding the endpoints cytotoxicity and barrier integrity. Whereas there are low transfer rates from the blood side to the CSF side, our results strongly indicate an active transfer of the organic mercury compounds out of the CSF.These results are the first to demonstrate an efflux of organic mercury compounds regarding the CNS and provide a completely new approach in the understanding of mercury compounds specific transport.

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Glutamate-Mediated Upregulation of the Multidrug Resistance Protein 2 in Porcine and Human Brain Capillaries

Cited by 23 publications

References 52 publications

Role of Transporters in Central Nervous System Drug Delivery and Blood-Brain Barrier Protection: Relevance to Treatment of Stroke

Role of Transporters in Central Nervous System Drug Delivery and Blood-Brain Barrier Protection: Relevance to Treatment of Stroke

Regulation of ABC efflux transporters at blood-brain barrier in health and neurological disorders

Blood-Cerebrospinal Fluid Barrier

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