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Research ArticleArticle

Seizure-Induced Up-Regulation of P-Glycoprotein at the Blood-Brain Barrier through Glutamate and Cyclooxygenase-2 Signaling

Björn Bauer, Anika M. S. Hartz, Anton Pekcec, Kathrin Toellner, David S. Miller and Heidrun Potschka
Molecular Pharmacology May 2008, 73 (5) 1444-1453; DOI: https://doi.org/10.1124/mol.107.041210
Björn Bauer
Laboratory of Pharmacology and Chemistry, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina (B.B., A.M.S.H., D.S.M.); Department of Pharmaceutical Sciences, College of Pharmacy, University of Minnesota, Duluth, Minnesota (B.B.); Department of Biochemistry and Molecular Biology, Medical School, University of Minnesota, Duluth, Minnesota (A.M.S.H.); Institute of Pharmacology, Toxicology, and Pharmacy, Ludwig-Maximilians-University, Munich, Germany (A.P., H.P.); and Institute of Pharmacology, Toxicology, and Pharmacy, University of Veterinary Medicine, Hannover, Germany (K.T.)
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Anika M. S. Hartz
Laboratory of Pharmacology and Chemistry, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina (B.B., A.M.S.H., D.S.M.); Department of Pharmaceutical Sciences, College of Pharmacy, University of Minnesota, Duluth, Minnesota (B.B.); Department of Biochemistry and Molecular Biology, Medical School, University of Minnesota, Duluth, Minnesota (A.M.S.H.); Institute of Pharmacology, Toxicology, and Pharmacy, Ludwig-Maximilians-University, Munich, Germany (A.P., H.P.); and Institute of Pharmacology, Toxicology, and Pharmacy, University of Veterinary Medicine, Hannover, Germany (K.T.)
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Anton Pekcec
Laboratory of Pharmacology and Chemistry, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina (B.B., A.M.S.H., D.S.M.); Department of Pharmaceutical Sciences, College of Pharmacy, University of Minnesota, Duluth, Minnesota (B.B.); Department of Biochemistry and Molecular Biology, Medical School, University of Minnesota, Duluth, Minnesota (A.M.S.H.); Institute of Pharmacology, Toxicology, and Pharmacy, Ludwig-Maximilians-University, Munich, Germany (A.P., H.P.); and Institute of Pharmacology, Toxicology, and Pharmacy, University of Veterinary Medicine, Hannover, Germany (K.T.)
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Kathrin Toellner
Laboratory of Pharmacology and Chemistry, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina (B.B., A.M.S.H., D.S.M.); Department of Pharmaceutical Sciences, College of Pharmacy, University of Minnesota, Duluth, Minnesota (B.B.); Department of Biochemistry and Molecular Biology, Medical School, University of Minnesota, Duluth, Minnesota (A.M.S.H.); Institute of Pharmacology, Toxicology, and Pharmacy, Ludwig-Maximilians-University, Munich, Germany (A.P., H.P.); and Institute of Pharmacology, Toxicology, and Pharmacy, University of Veterinary Medicine, Hannover, Germany (K.T.)
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David S. Miller
Laboratory of Pharmacology and Chemistry, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina (B.B., A.M.S.H., D.S.M.); Department of Pharmaceutical Sciences, College of Pharmacy, University of Minnesota, Duluth, Minnesota (B.B.); Department of Biochemistry and Molecular Biology, Medical School, University of Minnesota, Duluth, Minnesota (A.M.S.H.); Institute of Pharmacology, Toxicology, and Pharmacy, Ludwig-Maximilians-University, Munich, Germany (A.P., H.P.); and Institute of Pharmacology, Toxicology, and Pharmacy, University of Veterinary Medicine, Hannover, Germany (K.T.)
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Heidrun Potschka
Laboratory of Pharmacology and Chemistry, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina (B.B., A.M.S.H., D.S.M.); Department of Pharmaceutical Sciences, College of Pharmacy, University of Minnesota, Duluth, Minnesota (B.B.); Department of Biochemistry and Molecular Biology, Medical School, University of Minnesota, Duluth, Minnesota (A.M.S.H.); Institute of Pharmacology, Toxicology, and Pharmacy, Ludwig-Maximilians-University, Munich, Germany (A.P., H.P.); and Institute of Pharmacology, Toxicology, and Pharmacy, University of Veterinary Medicine, Hannover, Germany (K.T.)
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Abstract

Increased expression of drug efflux transporters at the blood-brain barrier accompanies epileptic seizures and complicates therapy with antiepileptic drugs. This study is concerned with identifying mechanistic links that connect seizure activity to increased P-glycoprotein expression at the blood-brain barrier. In this regard, we tested the hypothesis that seizures increase brain extracellular glutamate, which signals through an N-methyl-d-aspartate (NMDA) receptor and cyclooxygenase-2 (COX-2) in brain capillaries to increase blood-brain barrier P-glycoprotein expression. Consistent with this hypothesis, exposing isolated rat or mouse brain capillaries to glutamate for 15 to 30 min increased P-glycoprotein expression and transport activity hours later. These increases were blocked by 5H-dibenzo[a,d]cyclohepten-5,10-imine (dizocilpine maleate) (MK-801), an NMDA receptor antagonist, and by celecoxib, a selective COX-2 inhibitor; no such glutamate-induced increases were seen in brain capillaries from COX-2-null mice. In rats, intracerebral microinjection of glutamate caused locally increased P-glycoprotein expression in brain capillaries. Moreover, using a pilocarpine status epilepticus rat model, we observed seizure-induced increases in capillary P-glycoprotein expression that were attenuated by administration of indomethacin, a COX inhibitor. Our findings suggest that brain uptake of some antiepileptic drugs can be enhanced through COX-2 inhibition. Moreover, they provide insight into one mechanism that underlies drug resistance in epilepsy and possibly other central nervous system disorders.

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Molecular Pharmacology: 73 (5)
Molecular Pharmacology
Vol. 73, Issue 5
1 May 2008
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Research ArticleArticle

Seizure-Induced Up-Regulation of P-Glycoprotein at the Blood-Brain Barrier through Glutamate and Cyclooxygenase-2 Signaling

Björn Bauer, Anika M. S. Hartz, Anton Pekcec, Kathrin Toellner, David S. Miller and Heidrun Potschka
Molecular Pharmacology May 1, 2008, 73 (5) 1444-1453; DOI: https://doi.org/10.1124/mol.107.041210

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Research ArticleArticle

Seizure-Induced Up-Regulation of P-Glycoprotein at the Blood-Brain Barrier through Glutamate and Cyclooxygenase-2 Signaling

Björn Bauer, Anika M. S. Hartz, Anton Pekcec, Kathrin Toellner, David S. Miller and Heidrun Potschka
Molecular Pharmacology May 1, 2008, 73 (5) 1444-1453; DOI: https://doi.org/10.1124/mol.107.041210
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