Received for publication August 27, 2007.
Revised December 19, 2007.
Accepted for publication December 19, 2007.

Seizure-Induced Upregulation of P-glycoprotein at the Blood-Brain Barrier through Glutamate and COX-2 Signaling

Abstract

Increased expression of drug efflux transporters at the blood-brain barrier accompanies epileptic seizures and complicates therapy with antiepileptic drugs. The present 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 NMDA receptor and 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 15-30 min increased P-glycoprotein expression and transport activity hours later. These increases were blocked by 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 CNS disorders.

Key words: Glutamate, MDR/p-Glycoprotein, Cyclooxygenases

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