P-glycoprotein--a clinical target in drug-refractory epilepsy?
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. It is noteworthy that P-glycoprotein has been shown to be up-regulated 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 Pgp actually plays a role in drug-resistant epilepsy. In this issue of Molecular Pharmacology, Bauer et al. (p. 1444) demonstrate that glutamate can cause localized up-regulation of Pgp via cyclooxygenase-2 (COX-2) and that this phenomenon can be prevented with COX-2 inhibitors. Localized rather than global up-regulation 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.
Robey
Robert W
RW
Medical Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA. robeyr@mail.nih.gov
Lazarowski
Alberto
A
Bates
Susan E
SE
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics*; D000818:Animals; D002196:Capillaries / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D051546:Cyclooxygenase 2 / Q000378:metabolism; D018698:Glutamic Acid / Q000494:pharmacology; D051379:Mice; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D012640:Seizures / Q000139:chemically induced / Q000473:pathology*; D015854:Up-Regulation / Q000235:genetics
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D016194:Receptors, N-Methyl-D-Aspartate; D018698:Glutamic Acid; D051546:Cyclooxygenase 2