Received for publication February 26, 2008.
Revised February 25, 2008.
Accepted for publication February 26, 2008.

P-glycoprotein-a clinical target in drug-refractory epilepsy? (Relates to article by Bauer, et al., Fast Forward 19 Dec 2007)

Abstract

ATP-binding cassette transporters such as P-glycoprotein (Pgp), multidrug resistance-associated protein and breast cancer resistance protein are known to transport a wide range of substrates and are highly expressed in the capillary endothelial cells that form part of the blood-brain barrier. Interestingly, P-glycoprotein has been shown to be upregulated in animal models of refractory epilepsy and adding a Pgp inhibitor to treatment regimens has been shown to reverse the drug-resistant phenotype. Limited data have suggested a role for Pgp in epilepsy in humans as well. However, few epilepsy drugs have been shown to be transported by Pgp, leading to controversy over whether or not Pgp actually plays a role in drug-resistant epilepsy. In this issue of Molecular Pharmacology, Bauer and colleagues demonstrate that glutamate can cause localized upregulation of Pgp via COX-2, and that this phenomenon can be prevented with COX-2 inhibitors. Localized rather than global upregulation of Pgp may explain some of the difficulty investigators have had in proving a role for Pgp in epilepsy. The results add new support for future clinical trials targeting Pgp expression in drug-refractory epilepsy.

Key words: MDR/p-Glycoprotein, Immunocytochemistry