Celecoxib treatment restores pharmacosensitivity in a rat model of pharmacoresistant epilepsy

Br J Pharmacol. 2010 Jul;160(5):1062-71. doi: 10.1111/j.1476-5381.2010.00765.x.


Background and purpose: A functional link between seizure-induced P-glycoprotein overexpression at the blood-brain barrier and therapeutic failure has been suggested by several studies using rodent epilepsy models and human epileptic tissue. Recently, we reported that interference with the mechanisms that up-regulate P-glycoprotein in response to seizure activity might provide a novel approach to control its expression in the epileptic brain. Based on these data, we hypothesized that blocking the appropriate signalling cascade by cyclooxygenase-2 inhibition should improve brain penetration of antiepileptic drugs and help to overcome drug resistance.

Experimental approach: Effects of the selective cyclooxygenase-2 inhibitor celecoxib on the response to the P-glycoprotein substrate, phenobarbital, was evaluated in a chronic model of drug-resistant temporal lobe epilepsy in rats. Drug-resistant rats selected from this model exhibit a marked overexpression of P-glycoprotein in the hippocampus and other limbic brain regions.

Key results: Responders and non-responders were selected from a group of rats with spontaneous recurrent seizures after prolonged treatment with phenobarbital at maximum tolerated doses. The efficacy of phenobarbital was re-evaluated following a 6 day treatment with celecoxib and the frequency of spontaneous recurrent seizures was significantly reduced in both groups of rats, phenobarbital responders or non-responders selected from the previous drug trial.

Conclusions and implications: Pretreatment with the cyclooxygenase-2 inhibitor restored the anticonvulsant activity of phenobarbital in rats that failed to exhibit a relevant response before celecoxib treatment. Our data provide further support for a novel therapeutic approach to overcome transporter-mediated drug resistance in epilepsies.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism
  • Animals
  • Anticonvulsants / administration & dosage*
  • Anticonvulsants / pharmacokinetics
  • Brain / drug effects
  • Brain / metabolism
  • Celecoxib
  • Cyclooxygenase 2 Inhibitors / administration & dosage
  • Cyclooxygenase 2 Inhibitors / pharmacology*
  • Disease Models, Animal*
  • Drug Administration Schedule
  • Drug Resistance / drug effects*
  • Epilepsy, Temporal Lobe / drug therapy*
  • Epilepsy, Temporal Lobe / metabolism
  • Female
  • Phenobarbital / administration & dosage*
  • Phenobarbital / pharmacokinetics
  • Pyrazoles / administration & dosage
  • Pyrazoles / pharmacology*
  • Rats
  • Rats, Sprague-Dawley
  • Sulfonamides / administration & dosage
  • Sulfonamides / pharmacology*


  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • Anticonvulsants
  • Cyclooxygenase 2 Inhibitors
  • Pyrazoles
  • Sulfonamides
  • Celecoxib
  • Phenobarbital