COX-2 inhibition controls P-glycoprotein expression and promotes brain delivery of phenytoin in chronic epileptic rats
| Autor: | Peter M. Edelbroek, Linda Holtman, Anton Pekcec, Jan A. Gorter, Eleonora Aronica, Heidrun Potschka, Erwin A. van Vliet, Guido Zibell, Juli Schlichtiger |
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| Přispěvatelé: | Cellular and Computational Neuroscience (SILS, FNWI), Other departments, Amsterdam Neuroscience, Amsterdam Public Health, Neurology, Pathology |
| Rok vydání: | 2010 |
| Předmět: |
Male
Phenytoin Status epilepticus Pharmacology Blood–brain barrier Rats Sprague-Dawley 03 medical and health sciences Cellular and Molecular Neuroscience Epilepsy chemistry.chemical_compound Status Epilepticus 0302 clinical medicine Seizures Animals Medicine ATP Binding Cassette Transporter Subfamily B Member 1 Rats Wistar Nitrobenzenes 030304 developmental biology P-glycoprotein NS-398 Sulfonamides 0303 health sciences Cyclooxygenase 2 Inhibitors biology business.industry Glutamate receptor Brain Transporter medicine.disease Rats Disease Models Animal medicine.anatomical_structure chemistry Blood-Brain Barrier Cyclooxygenase 2 Chronic Disease biology.protein Pyrazoles Anticonvulsants Female medicine.symptom business 030217 neurology & neurosurgery Signal Transduction medicine.drug |
| Zdroj: | Neuropharmacology Neuropharmacology, 58(2), 404-412. Elsevier Neuropharmacology; Vol 58 Neuropharmacology, 58(2), 404-412. Elsevier Limited |
| ISSN: | 1873-7064 0028-3908 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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