British journal of pharmacology · 2010
Celecoxib treatment restores pharmacosensitivity in a rat model of pharmacoresistant epilepsy.
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Schlichtiger J, Pekcec A, Bartmann H, Winter P, Fuest C, Soerensen J, Potschka H
Аннотация
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.
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.