Regional Expression of Multidrug Resistance Genes in Genetically Epilepsy-prone Rat Brain after a Single Audiogenic Seizure

Authors


Address correspondence and reprint requests to Dr. G. J. Sills at Epilepsy Unit, Department of Medicine and Therapeutics, Western Infirmary, Glasgow G11 6NT, Scotland. E-mail: g.j.sills@clinmed.gla.ac.uk

Abstract

Summary:  Purpose: The multidrug resistance (mdr) gene family encodes the drug transport macromolecule P-glycoprotein (P-gp), which contributes to the functionality of the blood–brain barrier. Recent evidence suggests that P-gp–mediated drug extrusion may play a facilitatory role in refractory epilepsy. We investigated the regional expression of mdr genes in genetically epilepsy-prone rat (GEPR) brain after a single audiogenic seizure.

Methods: Three groups of adult male GEPRs (n = 5/group) were exposed to a seizure-inducing audiogenic stimulus and killed at 4 h, 24 h, and 7 days thereafter. A further group (n = 5) served as a stimulus-naïve control. Expression of mdr1a and mdr1b in distinct anatomic brain regions (cortex, midbrain, pons/medulla, hippocampus) was determined by quantitative reverse transcriptase–polymerase chain reaction (RT-PCR) in the presence of competitive internal standards.

Results: When compared with control, mdr1a expression in cortex and midbrain was significantly (p < 0.05) increased at 24 h after a single audiogenic seizure. Cortical mdr1a expression remained elevated at 7 days after stimulus. In contrast, mdr1a expression in pons/medulla and hippocampus was unchanged. The mdr1b isoform was quantifiable in hippocampus alone and not influenced by seizure activity.

Conclusions: These findings suggest that acute seizures in the GEPR can induce the expression of mdr genes. The pattern of increased expression appears to follow the anatomic pathway of audiogenic seizures in these animals, with initiation in the midbrain and propagation to the cortex. Further studies are required to investigate the effects of recurrent seizure activity and to characterise mdr expression in other experimental seizure models.

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