Document Detail


P-glycoprotein imaging in temporal lobe epilepsy: In vivo PET experiments with the Pgp substrate [(11) C]-verapamil.
MedLine Citation:
PMID:  23134497     Owner:  NLM     Status:  In-Data-Review    
Abstract/OtherAbstract:
Overexpression of the multidrug efflux transporter P-glycoprotein (Pgp) at the blood-brain barrier (BBB) is thought to be involved in pharmacoresistance in epilepsy by extruding antiepileptic drugs (AEDs) from their target site. To explore this hypothesis, positron emission tomography (PET) scans were performed with the Pgp substrate-verapamil (VPM) in animal models before and after status epilepticus (SE) and in patients with temporal lobe epilepsy (TLE) and healthy controls. In addition to baseline scans, a second VPM-PET scan was performed after administration of the Pgp inhibitor tariquidar (TQD), showing that VPM uptake at baseline and its increase after Pgp inhibition are reduced in animals following SE compared to baseline, and in refractory TLE relative to healthy controls. In animal models, brain regions with increased Pgp expression (cerebellum, thalamus, and hippocampus) showed reduced influx rate constants from blood to brain, K(1) , of the radiolabeled Pgp substrate relative to control animals. In human studies, preliminary findings are lower K(1) values in refractory compared to seizure-free patients and attenuated increase of K(1) for temporal lobe regions in patients with TLE compared to healthy controls. In summary, there is lower brain uptake of the Pgp substrate VPM in Pgp-rich areas of animals 2 days following SE, as well as lower increase in VPM brain uptake after TQD in patients with refractory TLE compared to healthy controls, supporting the hypothesis of increased cerebral Pgp function following prolonged seizures and as a mechanism contributing to drug resistance in refractory epilepsy. The observation of reduced VPM uptake in refractory compared to seizure-free patients with TLE is consistent with multiple mechanisms affecting Pgp function, including uncontrolled seizures.
Authors:
Maria Feldmann; Matthias Koepp
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Publication Detail:
Type:  Journal Article    
Journal Detail:
Title:  Epilepsia     Volume:  53 Suppl 6     ISSN:  1528-1167     ISO Abbreviation:  Epilepsia     Publication Date:  2012 Nov 
Date Detail:
Created Date:  2012-11-08     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  2983306R     Medline TA:  Epilepsia     Country:  United States    
Other Details:
Languages:  eng     Pagination:  60-3     Citation Subset:  IM    
Copyright Information:
Wiley Periodicals, Inc. © 2012 International League Against Epilepsy.
Affiliation:
Department of Clinical and Experimental Epilepsy, UCL Institute of Neurology, London, United Kingdom.
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