Ex vivo characterization of neuroinflammatory and neuroreceptor changes during epileptogenesis using candidate positron emission tomography biomarkers.
[en] ("[en] OBJECTIVE: Identification of patients at risk of developing epilepsy before the first spontaneous seizure may promote the development of preventive treatment providing opportunity to stop or slow down the disease.
METHODS: As development of novel radiotracers and on-site setup of existing radiotracers is highly time-consuming and expensive, we used dual-centre in vitro autoradiography as an approach to characterize the potential of innovative radiotracers in the context of epilepsy development. Using brain slices from the same group of rats, we aimed to characterise the evolution of neuroinflammation and expression of inhibitory and excitatory neuroreceptors during epileptogenesis using translational positron emission tomography (PET) tracers; 18 F-flumazenil (18 F-FMZ; GABAA receptor), 18 F-FPEB (metabotropic glutamate receptor 5; mGluR5), 18 F-flutriciclamide (translocator protein; TSPO, microglia activation) and 18 F-deprenyl (monoamine oxidase B, astroglia activation). Autoradiography images from selected time points after pilocarpine-induced status epilepticus (SE; baseline, 24 and 48 hours, 5, 10 and 15 days and 6 and 12-14 weeks after SE) were normalized to a calibration curve, co-registered to an MRI-based 2D region-of-interest atlas, and activity concentration (Bq/mm2 ) was calculated.
RESULTS: In epileptogenesis-associated brain regions, 18 F-FMZ and 18 F-FPEB showed an early decrease after SE. 18 F-FMZ decrease was maintained in the latent phase and further reduced in the chronic epileptic animals, while 18 F-FPEB signal recovered from day 10, reaching baseline levels in chronic epilepsy. 18 F-flutriciclamide showed an increase of activated microglia at 24 hours after SE, peaking at 5-15 days and decreasing during the chronic phase. On the other hand, 18 F-deprenyl autoradiography showed late astrogliosis, peaking in the chronic phase.
SIGNIFICANCE: Autoradiography revealed different evolution of the selected targets during epileptogenesis. Our results suggest an advantage of combined imaging of inter-related targets like glutamate and GABAA receptors, or microglia and astrocyte activation, in order to identify important interactions, especially when using PET imaging for the evaluation of novel treatments.","[en] ","")
Disciplines :
Chemistry Radiology, nuclear medicine & imaging
Author, co-author :
Bascuñana, Pablo ✱; Department of Nuclear Medicine, Hannover Medical School, Hannover, Germany
Gendron, Thibault ✱; Université de Liège - ULiège > Département de chimie (sciences) > Chimie organique-nucléaire ; Institute of Nuclear Medicine, University College London, London, UK ; Department of Chemistry, University College London, London, UK
Sander, Kerstin; Institute of Nuclear Medicine, University College London, London, UK ; Department of Chemistry, University College London, London, UK
Jahreis, Ina; Department of Nuclear Medicine, Hannover Medical School, Hannover, Germany ; Department of Pharmacology, Toxicology and Pharmacy, University of Veterinary Medicine, Hannover, Germany
Polyak, Andras; Department of Nuclear Medicine, Hannover Medical School, Hannover, Germany
Ross, Tobias L; Department of Nuclear Medicine, Hannover Medical School, Hannover, Germany
Bankstahl, Marion; Department of Pharmacology, Toxicology and Pharmacy, University of Veterinary Medicine, Hannover, Germany ; Institute for Laboratory Animal Science, Hannover Medical School, Hannover, Germany
Arstad, Erik; Institute of Nuclear Medicine, University College London, London, UK ; Department of Chemistry, University College London, London, UK
Bankstahl, Jens P ; Department of Nuclear Medicine, Hannover Medical School, Hannover, Germany
✱ These authors have contributed equally to this work.
Language :
English
Title :
Ex vivo characterization of neuroinflammatory and neuroreceptor changes during epileptogenesis using candidate positron emission tomography biomarkers.
FP7 - 602102 - EPITARGET - Targets and biomarkers for antiepileptogenesis
Name of the research project :
EPITARGET
Funders :
KAS - Konrad-Adenauer-Stiftung EU - European Union
Funding number :
602102
Funding text :
This study was funded by the European Seventh's Framework Programme (FP7/2007-2013) under grant agreement n°602102 (EPITARGET). I. Jahreis was supported by a scholarship from the Konrad-Adenauer-Stiftung e.V. We thank GE Healthcare for providing the general method and access to the precursor for 18F-flutriciclamide synthesis. K. Sander is funded by Mallinckrodt. This work was undertaken in part at UCLH/UCL, which is funded in part by the Department of Health's NIHR Biomedical Research Centres funding scheme.
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