COX-2 inhibition controls P-glycoprotein expression and promotes brain delivery of phenytoin in chronic epileptic rats.
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.
van Vliet
Erwin A
EA
Epilepsy Institute in The Netherlands Foundation (SEIN), Heemstede, The Netherlands.
Zibell
Guido
G
Pekcec
Anton
A
Schlichtiger
Juli
J
Edelbroek
Peter M
PM
Holtman
Linda
L
Aronica
Eleonora
E
Gorter
Jan A
JA
Potschka
Heidrun
H
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000818:Animals; D000927:Anticonvulsants / Q000493:pharmacokinetics*; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000378:metabolism; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D002908:Chronic Disease; D051546:Cyclooxygenase 2 / Q000378:metabolism; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology*; D004195:Disease Models, Animal; D004827:Epilepsy / Q000188:drug therapy / Q000378:metabolism; D005260:Female; D008297:Male; D009578:Nitrobenzenes / Q000494:pharmacology; D010672:Phenytoin / Q000493:pharmacokinetics*; D011720:Pyrazoles / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D012640:Seizures / Q000188:drug therapy / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013226:Status Epilepticus / Q000188:drug therapy* / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology; D000096926:Benzenesulfonamides
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000927:Anticonvulsants; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D009578:Nitrobenzenes; D010672:Phenytoin; D011720:Pyrazoles; D013449:Sulfonamides; C119130:4-(5-(4-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzenesulfonamide; D000096926:Benzenesulfonamides; C080955:N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide; C489691:Ptgs2 protein, rat