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Open Access Research article

(R)-[11C]Verapamil PET studies to assess changes in P-glycoprotein expression and functionality in rat blood-brain barrier after exposure to kainate-induced status epilepticus

Stina Syvänen1*, Gert Luurtsema2, Carla FM Molthoff3, Albert D Windhorst3, Marc C Huisman3, Adriaan A Lammertsma3, Rob A Voskuyl14 and Elizabeth C de Lange1

Author Affiliations

1 Division of Pharmacology, LACDR, Leiden University, P.O. Box 9502, 2300 RA Leiden, The Netherlands

2 Department of Nuclear Medicine & Molecular Imaging, Groningen University Medical Center, P.O. Box 30.001 9700 RB Groningen, The Netherlands

3 Department of Nuclear Medicine & PET Research, VU University Medical Center, P.O. Box 7057, 1007 MB, Amsterdam, The Netherlands

4 Epilepsy Institute of The Netherlands Foundation (SEIN), P.O. Box 21, 2100 AA, Heemstede, The Netherlands

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BMC Medical Imaging 2011, 11:1  doi:10.1186/1471-2342-11-1

Published: 3 January 2011

Abstract

Background

Increased functionality of efflux transporters at the blood-brain barrier may contribute to decreased drug concentrations at the target site in CNS diseases like epilepsy. In the rat, pharmacoresistant epilepsy can be mimicked by inducing status epilepticus by intraperitoneal injection of kainate, which leads to development of spontaneous seizures after 3 weeks to 3 months. The aim of this study was to investigate potential changes in P-glycoprotein (P-gp) expression and functionality at an early stage after induction of status epilepticus by kainate.

Methods

(R)-[11C]verapamil, which is currently the most frequently used positron emission tomography (PET) ligand for determining P-gp functionality at the blood-brain barrier, was used in kainate and saline (control) treated rats, at 7 days after treatment. To investigate the effect of P-gp on (R)-[11C]verapamil brain distribution, both groups were studied without or with co-administration of the P-gp inhibitor tariquidar. P-gp expression was determined using immunohistochemistry in post mortem brains. (R)-[11C]verapamil kinetics were analyzed with approaches common in PET research (Logan analysis, and compartmental modelling of individual profiles) as well as by population mixed effects modelling (NONMEM).

Results

All data analysis approaches indicated only modest differences in brain distribution of (R)-[11C]verapamil between saline and kainate treated rats, while tariquidar treatment in both groups resulted in a more than 10-fold increase. NONMEM provided most precise parameter estimates. P-gp expression was found to be similar for kainate and saline treated rats.

Conclusions

P-gp expression and functionality does not seem to change at early stage after induction of anticipated pharmacoresistant epilepsy by kainate.