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

• Published in: Molecular pharmacology Vol. 73; no. 5; pp. 1444 - 1453
• Main Authors: Bauer, Björn, Hartz, Anika M S, Pekcec, Anton, Toellner, Kathrin, Miller, David S, Potschka, Heidrun
• Format: Journal Article
• Language: English
• Published: United States American Society for Pharmacology and Experimental Therapeutics 01.05.2008
• Subjects: Animals; ATP-Binding Cassette, Sub-Family B, Member 1 - genetics; Blood-Brain Barrier - drug effects; Blood-Brain Barrier - enzymology; Blood-Brain Barrier - pathology; Capillaries - drug effects; Capillaries - enzymology; Capillaries - pathology; Cyclooxygenase 2 - metabolism; Female; Glutamic Acid - pharmacology; Hippocampus - drug effects; Hippocampus - enzymology; Indomethacin; Male; Mice; Mice, Inbred C57BL; Pilocarpine; Protein Biosynthesis - drug effects; Rats; Rats, Sprague-Dawley; Rats, Wistar; Receptors, N-Methyl-D-Aspartate - metabolism; Seizures - chemically induced; Seizures - pathology; Signal Transduction - drug effects; Transcription, Genetic - drug effects; Up-Regulation - genetics
• ISSN: 0026-895X; 1521-0111
• DOI: 10.1124/mol.107.041210

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 5 H -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.