Transient increase of P-glycoprotein expression in endothelium and parenchyma of limbic brain regions in the kainate model of temporal lobe epilepsy.
Several recent studies have shown that the multidrug transporter P-glycoprotein (PGP) is over-expressed in endothelial cells from brain blood vessels of patients with refractory temporal lobe epilepsy (TLE), suggesting that altered drug permeability across the blood-brain barrier (BBB) may be involved in pharmacoresistance to antiepileptic drugs (AEDs). Furthermore, over-expression of PGP has been found in astrocytes of epileptogenic tissue. However, it is not known in which regions of the temporal lobe PGP over-expression occurs and whether the over-expression is a result of uncontrolled seizures, of the mechanisms underlying epilepsy, or of chronic administration of AEDs. In the present study, we used the rat kainate model of TLE to study the time-course of PGP expression in capillary endothelium and parenchyma of the hippocampus and several other limbic brain regions thought to be involved in TLE. Kainate was administered at a dose which produced a generalized convulsive status epilepticus (SE), which was limited to a duration of 90 min by diazepam. PGP was detected by immunohistochemistry either 24 h or 10 days after SE, using a monoclonal PGP antibody. In both kainate-treated rats and controls, PGP staining was observed mainly in microvessel endothelial cells and, to a much lesser extent, in parenchymal cells. Twenty-four hours after SE, significant increases in PGP expression were determined in endothelial cells of the dentate gyrus and in parenchymal cells of the CA1 and CA3 sectors of the hippocampus. Furthermore, increased PGP expression was observed in the amygdala, piriform, and parietal cortex, but not in the substantia nigra. Ten days after the kainate-induced SE, except for an increase in parenchymal PGP expression in the dentate hilus and CA1 sector, no significant differences to controls were determined, indicating that most PGP increases seen 24 h after SE were only transient. The data indicate that PGP over-expression is a transient result of seizures and occurs in several regions of the temporal lobe. Seizure-induced over-expression of PGP in capillary endothelial cells of the BBB is likely to reduce the penetration of AEDs into brain parenchyma, which could explain the drug-refractoriness of seizures in TLE.
Seegers
Ulrike
U
Department of Pharmacology, Toxicology and Pharmacy, School of Veterinary Medicine, Bünteweg 17, Building 218, D-30559 Hannover, Germany.
Potschka
Heidrun
H
Löscher
Wolfgang
W
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000818:Animals; D001923:Brain Chemistry / Q000187:drug effects; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000737:chemistry* / Q000166:cytology / Q000187:drug effects; D004833:Epilepsy, Temporal Lobe / Q000139:chemically induced / Q000378:metabolism*; D005260:Female; D006624:Hippocampus / Q000166:cytology / Q000378:metabolism; D007150:Immunohistochemistry; D007608:Kainic Acid / Q000008:administration & dosage*; D008032:Limbic System / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D013997:Time Factors
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D007608:Kainic Acid