Upregulation of Multidrug Resistance Transporters in the Epileptic Brain.

Abstract

Limbic Seizures Induce P-glycoprotein in Rodent Brain: Functional Implications for Pharmacoresistance Rizzi M, Caccia S, Guiso G, Richichi C, Gorter JA, Aronica E, Aliprandi M, Bagnati R, Fanelli R, D'Incalci M, Samanin R, Vezzani A J Neurosci 2002;22:5833–5839 The causes and mechanisms underlying multidrug resistance (MDR) in epilepsy are still elusive and may depend on inadequate drug concentration in crucial brain areas. We studied whether limbic seizures or anticonvulsant drug (AED) treatments in rodents enhance the brain expression of the MDR gene ( mdr) encoding a permeability glycoprotein (P-gp) involved in MDR to various cancer chemotherapeutic agents. We also investigated whether changes in P-gp levels affect AED concentrations in the brain. Mdr mRNA measured by reverse transcriptase–polymerase chain reaction (RT-PCR) increased by 85% on average in the mouse hippocampus 3–24 h after kainic acid–induced limbic seizures, returning to control levels by 72 h. Treatment with therapeutic doses of phenytoin (PHT) or carbamazepine (CBZ) for 7 days did not change mdr mRNA expression in the mouse hippocampus 1–72 h after the last drug administration. Six hours after seizures, the brain/plasma ratio of PHT was reduced by 30%, and its extracellular concentration estimated by microdialysis was increased by twofold compared with control mice. Knockout mice (mdr1a/b_/_) lacking P-gp protein showed a 46% increase in PHT concentrations in the hippocampus 1 and 4 h after injection compared with wild-type mice. A significant 23% increase was found in the cerebellum at 1 h and in the cortex at 4 h. CBZ concentrations were measurable in the hippocampus at 3 h in mdr1a/b_/_mice, whereas they were undetectable at the same interval in wild-type mice. In rats having spontaneous seizures 3 months after electrically induced status epilepticus, mdr1 mRNA levels were enhanced by 1.8-fold and fivefold on average in the hippocampus and entorhinal cortex, respectively. Thus changes in P-gp mRNA levels occur in limbic areas after both acute and chronic epileptic activity. P-gp alterations significantly affect AED concentrations in the brain, suggesting that seizure-induced mdr mRNA expression contributes to MDR in epilepsy. Overexpression of Multiple Drug Resistance Genes in Endothelial Cells from Patients with Refractory Epilepsy Dombrowski SM, Desai SY, Marroni M, Cucullo L, Goodrich K, Bingaman W, Mayberg MR, Bengez L, Janigro D Epilepsia 2001;42:1501–1506 Purpose It has been suggested that altered drug permeability across the blood-brain barrier (BBB) may be involved in pharmacoresistance to antiepileptic drugs (AEDs). To test this hypothesis further, we measured multiple drug resistance (MDR) gene expression in endothelial cells (ECs) isolated from temporal lobe blood vessels of patients with refractory epilepsy. ECs from umbilical cord or temporal lobe vessels obtained from aneurysm surgeries were used as comparison tissue. Methods cDNA arrays were used to determine MDR expression. MDR protein (MRP1) immunocytochemistry and Western blot analysis were used to confirm cDNA array data. Results We found overexpression of selected MDR and significantly higher P-glycoprotein levels in “epileptic” versus “control” ECs. Specifically, MDR1, cMRP/MRP2, and MRP5 were upregulated in epileptic tissue, whereas Pgp3/MDR3 levels were comparable to those measured in comparison tissue. The gene encoding cisplatin resistance-associated protein (hCRA-α) also was Conclusions Complex MDR expression changes may play a role in AED pharmacoresistance by altering the permeability of AEDs across the BBB. overexpressed in epileptic tissue. Immunocytochemical analysis revealed that MDR1 immunoreactivity was localized primarily in ECs; MRP1 protein levels also were significantly higher in epileptic tissue.