COX-2 inhibition controls P-glycoprotein expression and promotes brain delivery of phenytoin in chronic epileptic rats
Introduction
Resistance to antiepileptic drugs continues to be a major challenge in the pharmacotherapy of epilepsy. Limitation of antiepileptic drug brain penetration is discussed as a putative contributor to therapeutic failure (Loscher and Potschka, 2005a). Several studies indicate that overexpression of blood–brain barrier efflux transporters occurs in response to epileptic seizure activity. Recently, it has been demonstrated that selective inhibition of the major efflux transporter P-glycoprotein (Pgp) enhances the brain uptake of antiepileptic drugs and improves the anticonvulsant response (Brandt et al., 2006, Clinckers et al., 2005, van Vliet et al., 2006). These findings point to a role of seizure-induced Pgp overexpression as a limiting factor in epilepsy pharmacotherapy.
Prevention of seizure-induced transporter overexpression may therefore render an elegant strategy to improve the outcome of antiepileptic drug therapy. Recently, we were able to identify cyclooxygenase as a central factor of a cascade that drives the transcriptional activation of the Pgp-encoding gene in the epileptic brain (Bauer et al., 2008). Cyclooxygenase-2 proved to mediate Pgp regulation in response to excess glutamate concentrations such as those occurring during epileptic seizures. In initial in vivo experiments, the non-selective COX inhibitor indomethacin as well as the COX-2 inhibitor celecoxib attenuated the status epilepticus-induced increase in capillary Pgp expression in the acute phase of the pilocarpine model (Bauer et al., 2008).
These data suggest that selective COX-2 inhibition constitutes a promising strategy to control Pgp expression despite recurrent seizure activity in the epileptic brain and to promote delivery of antiepileptic drugs to the brain. To test this hypothesis we determined the effect of selective COX-2 inhibition on Pgp expression and on phenytoin brain penetration in the chronic phase of a electrical post-status epilepticus model. In preparation for this experiment we evaluated the efficacy of two different highly-selective COX-2 inhibitors in the acute phase of two models with electrical or chemical induction of a status epilepticus.
Regarding our efforts to develop a preventive strategy it is of specific interest to further elucidate the complex mechanisms which drive Pgp expression in response to seizure activity. It has been speculated that enhanced expression of efflux transporters in the epileptic brain may represent a compensatory mechanism in response to a preceding seizure-associated leakiness of the blood–brain barrier. In line with this hypothesis, we addressed the question whether disturbance of BBB integrity triggers enhanced COX-2 signalling and subsequent induction of Pgp.
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Animals
Ninety-seven female Wistar Unilever rats and 103 male Sprague–Dawley rats (Harlan-Winkelmann, Borchen, Germany, and Harlan Netherlands, Horst, The Netherlands) were used in the present study. Animals were kept under controlled environmental conditions (22 ± 2 °C, 50–60% humidity, 12-h dark/light cycle) with free access to tap water and standard feed. Animals for experiments were allowed to adapt to the new environment for at least 1 week. All animal protocols were approved by the Institutional
Onset and course of status epilepticus
Seventy-two percent of NS-398 treated animals (n = 16 out of 22) developed a status epilepticus in response to repeated injections of the cholinomimetic pilocarpine. In the vehicle-treated group a status epilepticus was successfully induced in 63% of the animals (n = 20 out of 32). No significant difference was observed in the amount of pilocarpine required to induce a status epilepticus. In NS-398 treated rats a mean pilocarpine dosage of 39.4 ± 6.0 mg/kg was administered prior to onset of
Discussion
Our study demonstrates that selective COX-2 inhibition efficaciously controls Pgp expression in the epileptic brain. Consistent with these data selective COX-2 inhibition was substantiated as a promising strategy to promote delivery of the antiepileptic drug phenytoin to the brain.
Numerous studies have indicated that seizure-associated induction of the BBB efflux transporter Pgp is a common feature in a variety of acute seizure and chronic epilepsy models (Potschka et al., 2004, Rizzi et al.,
Acknowledgements
We acknowledge Pfizer for providing SC-58236, Merial for providing NS-398, Rien de Rijke and Wouter Dieters for phenytoin analysis in plasma and brain samples as well as Heidrun Zankl and Andrea Wehmeyer for their excellent technical assistance. This research was supported by the Epilepsy Institute in The Netherlands (SEIN)-Lopes da Silva fellowship (to EAvV), the EU-FP7-project NeuroGlia Grant Agreement No. 202167 (to EA), Nationaal Epilepsie Fonds grant 07-19 (to JG) and the grant DFG PO
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