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

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.)

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.

Address correspondence to: Dr. Heidrun Potschka, Institute of Pharmacology, Toxicology, and Pharmacy, Ludwig-Maximilians-University Munich, Koeniginstr. 16, 80539 Munich, Germany. E-mail: potschka{at}pharmtox.vetmed.uni-muenchen.de

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