Celecoxib treatment restores pharmacosensitivity in a rat model of pharmacoresistant epilepsy

Abstract

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.

Staged anticonvulsant screening for chronic epilepsy

“…The lack of efficacy of other COX2 inhibitors has further dampened enthusiasm for this anticonvulsant strategy 53. However, our data clarify that celecoxib is only efficacious in chronic epilepsy models, and a review of the prior mixed results also demonstrates that it is effective in in vivo chronic epilepsy models,48, 49, 50 but not acutely evoked seizures 48, 51, 52. We suggest that this may be a signature of a compound that would be effective for the one‐third of epilepsy patients who do not respond to currently available anticonvulsants, all of which were discovered by screening against acutely evoked seizures.…”

“…Celecoxib has previously been tested in several epilepsy models with quite mixed results 48, 49, 50, 51, 52. The lack of efficacy of other COX2 inhibitors has further dampened enthusiasm for this anticonvulsant strategy 53.…”

Drug Resistance and Resistance Mechanisms in Epilepsy

“…Nöbetle ilişkili P-gp indüksiyonunu önlemek için PGE2 EP1 reseptör antagonistleri ve COX2 inhibitörleri denenmektedir. [44,79,80] COX2 inhibisyonu ile kronik epileptik sıçanda, fenitoinin beyine penetrasyonun arttığı ve fenobarbitale duyarlılığının şekillendiği gözlenmiştir. [80] Bu ön-leyici stratejiler P-gp salınımını, bazal transport fonksiyonu bozulmayacak şekilde kontrollü olarak düzenler.…”

Modulation of Immunity and the Inflammatory Response: A New Target for Treating Drug-resistant Epilepsy

“…Moreover, COX-2 knockout mice are also resistant to neuronal death after KA treatment. Pretreatment with the COX-2 inhibitor restored the anticonvulsant activity of phenobarbital in rats that failed to exhibit a relevant response before celecoxib treatment [44]. However, endogenous IL-1β may also possess anticonvulsive properties, which may be mediated by arachidonic acid metabolites derived from the catalytic action of COX-2 [45].…”