(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

BMC Medical Imaging

Research Article

Gert Luurtsema¹  Adriaan A Lammertsma²  Albert D Windhorst²  Marc C Huisman²  Carla FM Molthoff²  Elizabeth C de Lange³  Stina Syvänen³  Rob A Voskuyl⁴ 

[1] Department of Nuclear Medicine & Molecular Imaging, Groningen University Medical Center, P.O. Box 30.001, 9700 RB, Groningen, The Netherlands;Department of Nuclear Medicine & PET Research, VU University Medical Center, P.O. Box 7057, 1007 MB, Amsterdam, The Netherlands;Division of Pharmacology, LACDR, Leiden University, P.O. Box 9502, 2300 RA, Leiden, The Netherlands;Division of Pharmacology, LACDR, Leiden University, P.O. Box 9502, 2300 RA, Leiden, The Netherlands;Epilepsy Institute of The Netherlands Foundation (SEIN), P.O. Box 21, 2100 AA, Heemstede, The Netherlands;

关键词: Positron Emission Tomography;    Verapamil;    Status Epilepticus;    Positron Emission Tomography Data;    Positron Emission Tomography Ligand;   

DOI  :  10.1186/1471-2342-11-1

 received in 2010-05-21, accepted in 2011-01-03,  发布年份 2011

来源: Springer

【 摘 要 】

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

【 授权许可】

CC BY   
© Syvänen et al; licensee BioMed Central Ltd. 2011