title: Neuronal expression of the drug efflux transporter P-glycoprotein in the rat hippocampus after limbic seizures.
abstract: In the brain, the efflux transporter P-glycoprotein (Pgp) is predominantly located on the luminal membrane of endothelial cells lining brain microvessels and forming the blood-brain barrier. Many lipophilic drugs, including antiepileptic drugs, are potential substrates for Pgp. Overexpression of Pgp in endothelial cells of the blood-brain barrier has been determined in patients with drug resistant forms of epilepsy such as temporal lobe epilepsy and rodent models of temporal lobe epilepsy and suggested to lead to reduced penetration of antiepileptic drugs into the brain. Expression of Pgp after seizures has also been described in astrocytes, whereas it is not clear whether neurons can express Pgp. In the present study, Pgp expression was studied by immunohistochemistry in rats 24 h after a status epilepticus induced by either pilocarpine or kainate, widely used models of temporal lobe epilepsy. Unexpectedly, in addition to endothelial Pgp staining, intense Pgp staining was found in neurons in the CA3c/CA4 sectors and hilus of the hippocampus formation, but not in other brain regions examined. The neuronal Pgp staining was confirmed by two different Pgp antibodies. Double immunolabeling and confocal microscopy showed that Pgp was colocalized with the neuronal marker neuronal nuclear antigen, but not with the glial marker glial fibrillary acidic protein. No neuronal Pgp staining was seen in control rats. The expression of Pgp in neurons after limbic seizures was substantiated by determining Pgp encoding genes (mdr1a, mdr1b) in neurons by real time quantitative RT-PCR. Increased Pgp expression in hippocampal neurons is likely to affect the action of drugs with intraneuronal targets and, in view of recent evidence from other cell types, could be associated with prevention of apoptosis which is involved in neuronal damage developing after seizures such as produced by pilocarpine.
authors.affiliation: Department of Pharmacology, Toxicology and Pharmacy, School of Veterinary Medicine, Bünteweg 17, D-30559, Hannover, Germany
authors.forename: H A
authors.initials: HA
authors.lastname: Volk
authors.forename: K
authors.initials: K
authors.lastname: Burkhardt
authors.forename: H
authors.initials: H
authors.lastname: Potschka
authors.forename: J
authors.initials: J
authors.lastname: Chen
authors.forename: A
authors.initials: A
authors.lastname: Becker
authors.forename: W
authors.initials: W
authors.lastname: Löscher
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000096:biosynthesis / Q000235:genetics; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000096:biosynthesis* / Q000235:genetics; D018528:ATP-Binding Cassette Transporters / Q000096:biosynthesis / Q000235:genetics; D000818:Animals; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism*; D007608:Kainic Acid / Q000633:toxicity; D008032:Limbic System / Q000187:drug effects / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D012640:Seizures / Q000139:chemically induced / Q000378:metabolism*; D000097202:ATP-Binding Cassette Sub-Family B Member 4
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D018528:ATP-Binding Cassette Transporters; D007608:Kainic Acid; D000097202:ATP-Binding Cassette Sub-Family B Member 4; C095122:multidrug resistance protein 3