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- Title
A Novel Positron Emission Tomography Imaging Protocol Identifies Seizure-Induced Regional Overactivity of P-Glycoprotein at the Blood-Brain Barrier.
- Authors
Bankstahl, Jens P.; Bankstahl, Marion; Kuntner, Claudia; Stanek, Johann; Wanek, Thomas; Meier, Martin; Ding, Xiao-Qi; Müller, Markus; Langer, Oliver; Löscher, Wolfgang
- Abstract
Approximately one-third of epilepsy patients are pharmacoresistant. Overexpression of P-glycoprotein and other multidrug transporters at the blood-brain barrier is thought to play an important role in drug-refractory epilepsy. Thus, quantification of regionally different P-glycoprotein activity in the brain in vivo is essential to identify P-glycoprotein overactivity as the relevant mechanism for drug resistance in an individual patient. Using the radiolabeled P-glycoprotein substrate (R)-[11C]verapamil and different doses of coadministered tariquidar, which is an inhibitor of P-glycoprotein, we evaluated whether small-animal positron emission tomography can quantify regional changes in transporter function in the ratbrain at baseline and 48 h after apilocarpine-induced status epilepticus. P-glycoprotein expression was additionally quantified by immunohistochemistry. To reveal putative seizure-induced changes in blood-brain barrier integrity, we performed gadolinium-enhanced magneticresonance scansona 7.0 tesla small-animal scanner. Before P-glycoprotein modulation, brainuptakeof (R)-[11C]verapamilwaslowin all regions investigated in controlandpost-status epilepticus rats. After administration of 3mg/kg tariquidar, which inhibits P-glycoproteinonly partially,we observed increased regional differentiation in brain activity uptake in post-status epilepticus versus control rats, which diminished after maximal P-glycoprotein inhibition. Regional increases in the efflux rate constant k2 , but not in distribution volume VT or influx rate constant K1 , correlated significantly with increases in P-glycoprotein expression measured by immunohistochemistry. This imaging protocol proves to be suitable to detect seizure-induced regional changes in P-glycoprotein activity and is readily applicable to humans, with the aim to detect relevant mechanisms of pharmacoresistance in epilepsy in vivo.
- Subjects
POSITRON emission tomography; MEDICAL imaging systems; DEVELOPMENTAL disabilities; GLYCOPROTEINS; P-glycoprotein
- Publication
Journal of Neuroscience, 2011, Vol 31, Issue 24, p8803
- ISSN
0270-6474
- Publication type
Article
- DOI
10.1523/JNEUROSCI.6616-10.2011