Imaging of P-glycoprotein-mediated pharmacoresistance in the hippocampus: Proof-of-concept in a chronic rat model of temporal lobe epilepsy

Authors: Bartmann, Hero; Fuest, Christina; la Fougere, Christian¹; Xiong, Guoming¹; Just, Theresa¹; Schlichtiger, Juli²; Winter, Petra²; Böning, Guido¹; Wängler, Björn¹; Pekcec, Anton²; Soerensen, Jonna²; Bartenstein, Peter¹; Cumming, Paul¹; Potschka, Heidrun²

Source: Epilepsia, Volume 51, Number 9, September 2010 , pp. 1780-1790(11)

Publisher: Wiley-Blackwell

Abstract:

Summary Purpose: 

Based on experimental findings, overexpression of P-glycoprotein at the blood-brain barrier has been suggested to be a contributor to pharmacoresistance of the epileptic brain. We test a technique for evaluation of interindividual differences of elevated transporter function, through microPET analysis of the impact of the P-glycoprotein modulator tariquidar. The preclinical study is intended for eventual translation to clinical research of patients with pharmacoresistant seizure disorders. Methods: 

We made a microPET evaluation of the effects of tariquidar on the brain kinetics of the P-glycoprotein substrate [¹⁸F]MPPF in a rat model with spontaneous recurrent seizures, in which it has previously been demonstrated that phenobarbital nonresponders exhibit higher P-glycoprotein expression than do phenobarbital responders. Results: 

Mean baseline parametric maps of the [¹⁸F]MPPF unidirectional blood-brain clearance (K₁; ml/g per min) and the efflux rate constant (k₂; per min) did not differ between the nonresponder and responder group. Tariquidar pretreatment increased the magnitude of [¹⁸F]MPPF K₁ in hippocampus by a mean of 142% in the nonresponders, which significantly exceeded the 92% increase observed in the responder group. The same treatment decreased the mean magnitude of [¹⁸F]MPPF k₂ in hippocampus by 27% in nonresponders, without comparable effects in the responder group. Discussion: 

These results constitute a proof-of-concept for a novel imaging approach to evaluate blood-brain barrier P-glycoprotein function in animals. By extension, [¹⁸F]MPPF positron emission tomography (PET) with tariquidar pretreatment may be amenable for clinical applications exploring further the relevance of P-glycoprotein overexpression, and for enabling the rational design of pharmacotherapy according to individual differences in P-glycoprotein expression.

Keywords: Positron emission tomography; P-glycoprotein; Multidrug transporter; Blood-brain barrier; Pharmacoresistance; Drug-refractoriness

Document Type: Research article

DOI: http://dx.doi.org/10.1111/j.1528-1167.2010.02671.x

Affiliations: 1: Department of Nuclear Medicine, Ludwig-Maximilians-University of Munich, Germany 2: Institute of Pharmacology, Toxicology, and Pharmacy, Ludwig-Maximilians-University, Munich, Germany

Publication date: 2010-09-01

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• In this Subject: Neurology & Psychiatry
• By this author: Bartmann, Hero ;  Fuest, Christina ;  la Fougere, Christian ;  Xiong, Guoming ;  Just, Theresa ;  Schlichtiger, Juli ;  Winter, Petra ;  Böning, Guido ;  Wängler, Björn ;  Pekcec, Anton ;  Soerensen, Jonna ;  Bartenstein, Peter ;  Cumming, Paul ;  Potschka, Heidrun

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