PT  - JOURNAL ARTICLE
AU  - Björn Bauer
AU  - Anika M. S. Hartz
AU  - Anton Pekcec
AU  - Kathrin Toellner
AU  - David S. Miller
AU  - Heidrun Potschka
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.