PT - JOURNAL ARTICLE AU - Bauer, Björn AU - Hartz, Anika M. S. AU - Pekcec, Anton AU - Toellner, Kathrin AU - Miller, David S. AU - Potschka, Heidrun TI - Seizure-Induced Up-Regulation of P-Glycoprotein at the Blood-Brain Barrier through Glutamate and Cyclooxygenase-2 Signaling AID - 10.1124/mol.107.041210 DP - 2008 May 01 TA - Molecular Pharmacology PG - 1444--1453 VI - 73 IP - 5 4099 - http://molpharm.aspetjournals.org/content/73/5/1444.short 4100 - http://molpharm.aspetjournals.org/content/73/5/1444.full SO - Mol Pharmacol2008 May 01; 73 AB - 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.