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

Neuropharmacology. 2009 Apr;56(5):849-55. doi: 10.1016/j.neuropharm.2009.01.009. Epub 2009 Jan 21.


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.

Publication types

  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / biosynthesis*
  • Animals
  • Arachidonic Acid / pharmacology
  • Arachidonic Acid / physiology
  • Blood-Brain Barrier / metabolism
  • Brain / blood supply*
  • Capillaries / drug effects
  • Capillaries / metabolism
  • Celecoxib
  • Cyclooxygenase 2 / biosynthesis*
  • Cyclooxygenase 2 Inhibitors / pharmacology*
  • Glutamic Acid / pharmacology
  • In Vitro Techniques
  • Male
  • Nitrobenzenes / pharmacology
  • Protein Transport
  • Pyrazoles / pharmacology
  • Rats
  • Rats, Sprague-Dawley
  • Status Epilepticus / metabolism*
  • Sulfonamides / pharmacology
  • Up-Regulation


  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • Cyclooxygenase 2 Inhibitors
  • Nitrobenzenes
  • Pyrazoles
  • Sulfonamides
  • N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide
  • Arachidonic Acid
  • Glutamic Acid
  • Cyclooxygenase 2
  • Celecoxib