title: (R)-[11C]PK11195 brain uptake as a biomarker of inflammation and antiepileptic drug resistance: evaluation in a rat epilepsy model.
abstract: Neuroinflammation has been suggested as a key determinant of the intrinsic severity of epilepsy. Glial cell activation and associated inflammatory signaling can influence seizure thresholds as well as the pharmacodynamics and pharmacokinetics of antiepileptic drugs. Based on these data, we hypothesized that molecular imaging of microglia activation might serve as a tool to predict drug refractoriness of epilepsy. Brain uptake of (R)-[11C]PK11195, a ligand of the translocator protein 18 kDa and molecular marker of microglia activation, was studied in a chronic model of temporal lobe epilepsy in rats with selection of phenobarbital responders and non-responders. In rats with drug-sensitive epilepsy, (R)-[11C]PK11195 brain uptake values were comparable to those in non-epileptic controls. Analysis in non-responders revealed enhanced brain uptake of up to 39% in different brain regions. The difference might be related to the fact that non-responders exhibited higher baseline seizure frequencies than responders indicating a more pronounced intrinsic disease severity. In hippocampal sections, ED1 immunostaining argued against a general difference in microglia activation between both groups. Our data suggest that TSPO PET imaging might serve as a biomarker for drug resistance in temporal lobe epilepsy. However, it needs to be considered that our findings indicate that the TSPO PET data might merely reflect seizure frequency. Future experimental and clinical studies should further evaluate the validity of TSPO PET data to predict the response to phenobarbital and other antiepileptic drugs in longitudinal studies with scanning before drug exposure and with a focus on the early phase following an epileptogenic brain insult.
authors.affiliation: Institute of Pharmacology, Toxicology & Pharmacy, Ludwig-Maximilians-University, Munich, Germany; Graduate School of Systemic Neurosciences, Ludwig-Maximilians-University, Munich, Germany.
authors.forename: Renée Marie
authors.initials: RM
authors.lastname: Bogdanović
authors.affiliation: Department of Public Health and Caring Sciences, Uppsala University, Uppsala, Sweden.
authors.forename: Stina
authors.initials: S
authors.lastname: Syvänen
authors.affiliation: Institute of Pharmacology, Toxicology & Pharmacy, Ludwig-Maximilians-University, Munich, Germany.
authors.forename: Christina
authors.initials: C
authors.lastname: Michler
authors.affiliation: Institute of Pharmacology, Toxicology & Pharmacy, Ludwig-Maximilians-University, Munich, Germany.
authors.forename: Vera
authors.initials: V
authors.lastname: Russmann
authors.affiliation: Department Medicinal Chemistry, Preclinical PET Platform, Uppsala University, Sweden.
authors.forename: Jonas
authors.initials: J
authors.lastname: Eriksson
authors.affiliation: Department of Radiology & Nuclear Medicine, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Albert D
authors.initials: AD
authors.lastname: Windhorst
authors.affiliation: Department of Radiology & Nuclear Medicine, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Adriaan A
authors.initials: AA
authors.lastname: Lammertsma
authors.affiliation: Division of Pharmacology, LACDR, Leiden University, Leiden, The Netherlands.
authors.forename: Elisabeth C
authors.initials: EC
authors.lastname: de Lange
authors.affiliation: Division of Pharmacology, LACDR, Leiden University, Leiden, The Netherlands; SEIN - Epilepsy Institutes of The Netherlands Foundation, Heemstede, The Netherlands.
authors.forename: Rob A
authors.initials: RA
authors.lastname: Voskuyl
authors.affiliation: Institute of Pharmacology, Toxicology & Pharmacy, Ludwig-Maximilians-University, Munich, Germany. Electronic address: potschka@pharmtox.vetmed.uni-muenchen.de.
authors.forename: Heidrun
authors.initials: H
authors.lastname: Potschka
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000097:blood / Q000494:pharmacology*; D001921:Brain / Q000000981:diagnostic imaging* / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology*; D002250:Carbon Radioisotopes; D002352:Carrier Proteins / Q000378:metabolism; D002908:Chronic Disease; D004195:Disease Models, Animal; D004351:Drug Resistance / Q000502:physiology; D004567:Electrodes, Implanted; D004833:Epilepsy, Temporal Lobe / Q000000981:diagnostic imaging* / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology*; D005260:Female; D007546:Isoquinolines; D017628:Microglia / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D015213:Neuroimmunomodulation / Q000502:physiology; D010634:Phenobarbital / Q000097:blood / Q000494:pharmacology*; D049268:Positron-Emission Tomography; D019275:Radiopharmaceuticals; D011897:Random Allocation; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000378:metabolism; D013226:Status Epilepticus / Q000000981:diagnostic imaging / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology
chemical_list: D000927:Anticonvulsants; D002250:Carbon Radioisotopes; D002352:Carrier Proteins; D007546:Isoquinolines; D019275:Radiopharmaceuticals; D011963:Receptors, GABA-A; C069997:Tspo protein, rat; C037850:PK 11195; D010634:Phenobarbital
keywords: (R)-[(11)C]PK11195; Drug refractoriness; Neuroinflammation; Pharmacoresistance; Positron emission tomography; Translocator protein 18 kDa