Selective and persistent upregulation of mdr1b mRNA and P-glycoprotein in the parahippocampal cortex of chronic epileptic rats.
There is recent evidence that increased expression of multidrug transporters, such as P-glycoprotein (P-gp), may lead to reduced antiepileptic drug (AED) concentrations in the brain, shortly after status epilepticus (SE), thereby suggesting a possible mechanism for drug-resistance. To get insights on whether increased P-gp expression is a consequence of the initial insult, or evolves more gradually as a result of recurrent spontaneous seizures, we used a rat model of temporal lobe epilepsy in which spontaneous seizures develop after an electrically induced SE. We investigated the temporal and region-specific expression of two isoforms of the multidrug resistance gene (mdr1a and mdr1b, both encoding for P-gp) in two regions within the temporal lobe (the dentate gyrus (DG) and the parahippocampal cortex (PHC)). Using real-time PCR, we found that the mdr1b isoform was increased in the temporal lobe, 1 week after SE; however, this increase was reversible in dentate gyrus while it persisted in the parahippocampal cortex of chronic epileptic rats. Mdr1b upregulation was related to the occurrence of spontaneous seizures, since this isoform was unchanged in rats that were stimulated, but that did not develop SE (non-SE). The mdr1a isoform was transiently upregulated in the dentate gyrus. P-gp immunostaining was enhanced in endothelial and glia-like cells, 1 week after SE. In chronic epileptic rats, the number of strongly P-gp positive glia-like cells was much lower than 1 week after SE, and it was mainly present in the most ventral part of the temporal lobe. These cells were in close apposition to strongly stained blood vessels. These findings show that both mdr1a and mdr1b are induced by SE, although the increase in mdr1b isoform was more persistent. More importantly, increased P-gp expression is still present in chronic epileptic rats.
van Vliet
Erwin
E
Stichting Epilepsie Instellingen Nederland, Achterweg 5, 2103 SW Heemstede, The Netherlands.
Aronica
Eleonora
E
Redeker
Sandra
S
Marchi
Nicola
N
Rizzi
Massimo
M
Vezzani
Annamaria
A
Gorter
Jan
J
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; D002908:Chronic Disease; D017931:DNA Primers; D018076:DNA, Complementary / Q000096:biosynthesis / Q000235:genetics; D018891:Dentate Gyrus / Q000378:metabolism; D004558:Electric Stimulation; D004567:Electrodes, Implanted; D004569:Electroencephalography; D004833:Epilepsy, Temporal Lobe / Q000235:genetics* / Q000378:metabolism*; D008297:Male; D020534:Parahippocampal Gyrus / Q000378:metabolism*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012008:Recurrence; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012640:Seizures / Q000378:metabolism; D015854:Up-Regulation; D000097202:ATP-Binding Cassette Sub-Family B Member 4
D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D018528:ATP-Binding Cassette Transporters; D017931:DNA Primers; D018076:DNA, Complementary; D012333:RNA, Messenger; D000097202:ATP-Binding Cassette Sub-Family B Member 4; C095122:multidrug resistance protein 3