COX-2 inhibition controls P-glycoprotein expression and promotes brain delivery of phenytoin in chronic epileptic rats.

Abstract

Epileptic seizures drive expression of the blood-brain barrier efflux transporter P-glycoprotein via a glutamate/cyclooxygenase-2 mediated signalling pathway. Targeting this pathway may represent an innovative approach to control P-glycoprotein expression in the epileptic brain and to enhance brain delivery of antiepileptic drugs. Therefore, we tested the effect of specific cyclooxygenase-2 inhibition on P-glycoprotein expression in two different status epilepticus models. Moreover, the impact of a cyclooxygenase-2 inhibitor on expression of the efflux transporter and on brain delivery of an antiepileptic drug was evaluated in rats with recurrent spontaneous seizures. The highly selective cyclooxygenase-2 inhibitors SC-58236 and NS-398 both counteracted the status epilepticus-associated increase in P-glycoprotein expression in the parahippocampal cortex and the ventral hippocampus. In line with our working hypothesis, a sub-chronic 2-week treatment with SC-58236 in the chronic epileptic state kept P-glycoprotein expression at control levels. As described previously, enhanced P-glycoprotein expression in chronic epileptic rats was associated with a significant reduction in the brain penetration of the antiepileptic drug phenytoin. Importantly, the brain delivery of phenytoin was significantly enhanced by sub-chronic cyclooxygenase-2 inhibition in rats with recurrent seizures. In conclusion, the data substantiate targeting of cyclooxygenase-2 in the chronic epileptic brain as a promising strategy to control the expression levels of P-glycoprotein despite recurrent seizure activity. Cyclooxygenase-2 inhibition may therefore help to increase concentrations of antiepileptic drugs at the target sites in the epileptic brain. It needs to be further evaluated whether the approach also enhances efficacy.

• Authors: Erwin A van Vliet, Guido Zibell, Anton Pekcec, Juli Schlichtiger, Peter M Edelbroek, Linda Holtman, Eleonora Aronica, Jan A Gorter, Heidrun Potschka
• Journal: Neuropharmacology (Neuropharmacology) Vol. 58 Issue 2 Pg. 404-12 (Feb 2010) ISSN: 1873-7064 [Electronic] England
• PMID: 19786037 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: 2009 Elsevier Ltd. All rights reserved.

Chemical References

• 4-(5-(4-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzenesulfonamide
• ATP Binding Cassette Transporter, Subfamily B, Member 1
• Anticonvulsants
• Cyclooxygenase 2 Inhibitors
• Nitrobenzenes
• Pyrazoles
• Sulfonamides
• N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide
• Phenytoin
• Cyclooxygenase 2
• Ptgs2 protein, rat

Topics

• ATP Binding Cassette Transporter, Subfamily B, Member 1 (metabolism)
• Animals
• Anticonvulsants (pharmacokinetics)
• Blood-Brain Barrier (drug effects, metabolism)
• Brain (drug effects, metabolism)
• Chronic Disease
• Cyclooxygenase 2 (metabolism)
• Cyclooxygenase 2 Inhibitors (pharmacology)
• Disease Models, Animal
• Epilepsy (drug therapy, metabolism)
• Female
• Male
• Nitrobenzenes (pharmacology)
• Phenytoin (pharmacokinetics)
• Pyrazoles (pharmacology)
• Rats
• Rats, Sprague-Dawley
• Rats, Wistar
• Seizures (drug therapy, metabolism)
• Signal Transduction (drug effects)
• Status Epilepticus (drug therapy, metabolism)
• Sulfonamides (pharmacology)