Seizure-induced up-regulation of P-glycoprotein at the blood-brain barrier through glutamate and cyclooxygenase-2 signaling.
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.
Bauer
Björn
B
Institute of Pharmacology, Toxicology, and Pharmacy, Ludwig-Maximilians-University Munich, Koeniginstr. 16, 80539 Munich, Germany.
Hartz
Anika M S
AM
Pekcec
Anton
A
Toellner
Kathrin
K
Miller
David S
DS
Potschka
Heidrun
H
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics*; D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D002196:Capillaries / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D005260:Female; D018698:Glutamic Acid / Q000494:pharmacology*; D006624:Hippocampus / Q000187:drug effects / Q000201:enzymology; D007213:Indomethacin; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010862:Pilocarpine; D014176:Protein Biosynthesis / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D012640:Seizures / Q000139:chemically induced / Q000473:pathology*; D015398:Signal Transduction / Q000187:drug effects*; D014158:Transcription, Genetic / Q000187:drug effects; D015854:Up-Regulation / Q000235:genetics*
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D016194:Receptors, N-Methyl-D-Aspartate; D010862:Pilocarpine; D018698:Glutamic Acid; D051546:Cyclooxygenase 2; D007213:Indomethacin