Prevention of seizure-induced up-regulation of endothelial P-glycoprotein by COX-2 inhibition

Guido Zibell, Bernadette Unkrüer, Anton Pekcec, Anika M.S. Hartz, Björn Bauer, David S. Miller, Heidrun Potschka

Research output: Contribution to journalArticlepeer-review

117 Scopus citations

Abstract

In the epileptic brain, seizure activity induces expression of the blood-brain barrier efflux transporter, P-glycoprotein, thereby limiting brain penetration and therapeutic efficacy of antiepileptic drugs. We recently provided the first evidence that seizures drive P-glycoprotein induction through a pathway that involves glutamate-signaling through the NMDA receptor and cyclooxygenase-2 (COX-2). Based on these data, we hypothesized that selective inhibition of COX-2 could prevent seizure-induced P-glycoprotein up-regulation. In the present study, we found that the highly selective COX-2 inhibitors, NS-398 and indomethacin heptyl ester, blocked the glutamate-induced increase in P-glycoprotein expression and transport function in isolated rat brain capillaries. Importantly, consistent with this, the COX-2 inhibitor, celecoxib, blocked seizure-induced up-regulation of P-glycoprotein expression in brain capillaries of rats in vivo. To explore further the role of COX-2 in signaling P-glycoprotein induction, we analyzed COX-2 protein expression in capillary endothelial cells in brain sections from rats that had undergone pilocarpine-induced seizures and in isolated capillaries exposed to glutamate and found no change from control levels. However, in isolated rat brain capillaries, the COX-2 substrate, arachidonic acid, significantly increased P-glycoprotein transport activity and expression indicating that enhanced substrate flux to COX-2 rather than increased COX-2 expression drives P-glycoprotein up-regulation. Together, these results provide the first in vivo proof-of-principle that specific COX-2 inhibition may be used as a new therapeutic strategy to prevent seizure-induced P-glycoprotein up-regulation at the blood-brain barrier for improving pharmacotherapy of drug-resistant epilepsy.

Original languageEnglish
Pages (from-to)849-855
Number of pages7
JournalNeuropharmacology
Volume56
Issue number5
DOIs
StatePublished - Apr 2009

Bibliographical note

Funding Information:
We thank Sylvia Notenboom and Christina Fuest for their excellent technical assistance. This research was supported by the grant DFG PO 681/4-1 (to HP) from the German Research Foundation, by a University of Minnesota GIA grant #20919 (to BB) and by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences.

Keywords

  • Cyclooxygenase-2
  • Epilepsy
  • Multidrug transporter
  • P-glycoprotein
  • Pharmacoresistance
  • Status epilepticus

ASJC Scopus subject areas

  • Pharmacology
  • Cellular and Molecular Neuroscience

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