title: A novel positron emission tomography imaging protocol identifies seizure-induced regional overactivity of P-glycoprotein at the blood-brain barrier.
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)-[(11)C]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 rat brain at baseline and 48 h after a pilocarpine-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 magnetic resonance scans on a 7.0 tesla small-animal scanner. Before P-glycoprotein modulation, brain uptake of (R)-[(11)C]verapamil was low in all regions investigated in control and post-status epilepticus rats. After administration of 3 mg/kg tariquidar, which inhibits P-glycoprotein only 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 k(2), but not in distribution volume V(T) or influx rate constant K(1), 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.
authors.affiliation: Department of Pharmacology, University of Veterinary Medicine, and Center for Systems Neuroscience, 30559 Hannover, Germany. jens.bankstahl@tiho-hannover.de
authors.forename: Jens P
authors.initials: JP
authors.lastname: Bankstahl
authors.forename: Marion
authors.initials: M
authors.lastname: Bankstahl
authors.forename: Claudia
authors.initials: C
authors.lastname: Kuntner
authors.forename: Johann
authors.initials: J
authors.lastname: Stanek
authors.forename: Thomas
authors.initials: T
authors.lastname: Wanek
authors.forename: Martin
authors.initials: M
authors.lastname: Meier
authors.forename: Xiao-Qi
authors.initials: XQ
authors.lastname: Ding
authors.forename: Markus
authors.initials: M
authors.lastname: Müller
authors.forename: Oliver
authors.initials: O
authors.lastname: Langer
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Löscher
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000704:Analysis of Variance; D000818:Animals; D019540:Area Under Curve; D001812:Blood-Brain Barrier / Q000000981:diagnostic imaging / Q000187:drug effects / Q000378:metabolism*; D002121:Calcium Channel Blockers / Q000493:pharmacokinetics; D002247:Carbon Isotopes / Q000493:pharmacokinetics; D003198:Computer Simulation; D004195:Disease Models, Animal; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D006571:Heterocyclic Compounds; D008279:Magnetic Resonance Imaging / Q000379:methods; D008956:Models, Chemical; D009942:Organometallic Compounds; D010862:Pilocarpine / Q000633:toxicity; D049268:Positron-Emission Tomography; D011804:Quinolines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012601:Scopolamine / Q000633:toxicity; D012640:Seizures / Q000139:chemically induced / Q000000981:diagnostic imaging* / Q000473:pathology*; D013997:Time Factors; D014700:Verapamil / Q000493:pharmacokinetics
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D002121:Calcium Channel Blockers; D002247:Carbon Isotopes; D006571:Heterocyclic Compounds; D009942:Organometallic Compounds; D011804:Quinolines; D010862:Pilocarpine; C050823:gadolinium 1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetate; D014700:Verapamil; D012601:Scopolamine; C402343:tariquidar