Skip to main content
SpringerLink
Log in

Präklinische Positronen-Emissions-Tomographie-Studien in Epilepsiemodellen

Fenster zur Zukunft in der Epilepsieforschung

Preclinical positron emission tomography studies in epilepsy models

Window to the future of epilepsy research

  • Leitthema
  • Published:
Zeitschrift für Epileptologie Aims and scope Submit manuscript

Zusammenfassung

Die Entstehungsmechanismen von Epilepsien und der damit häufig verbundenen Pharmakoresistenz sind bisher nicht ausreichend geklärt, und Tiermodelle sind nach wie vor zur Untersuchung der zugrunde liegenden pathologischen Mechanismen unabdingbar. Die Positronen-Emissions-Tomographie (PET) ist eine nichtinvasive nuklearmedizinische Methode, die die Visualisierung neurobiologischer Prozesse mithilfe radioaktiv markierter Tracer ermöglicht und somit ein wertvolles Werkzeug für die klinische sowie die präklinische Epilepsieforschung darstellt. Die gezielte Entwicklung von Kleintier-PET-Scannern erlaubt mittlerweile die umfassende Untersuchung von Ratten- und Maus-Epilepsie-Modellen über den gesamten Verlauf der Epileptogenese hinweg. Obwohl prinzipiell unbegrenzte Möglichkeiten für Molekülmarkierungen bestehen, wird in der Epilepsieforschung bisher überwiegend auf 2-[18F]Fluor-2-desoxy-D-Glucose ([18F]FDG), ein Tracer für den Glucoseverbrauch, zurückgegriffen. Die Entwicklung neuer PET-Tracer und deren präklinische Evaluierung als Biomarker für epileptogenese- sowie anfallsassoziierte Prozesse werden im Fokus zukünftiger Forschungsanstrengungen stehen. Solche Biomarker können zudem ein geeignetes Werkzeug zur Prüfung des Erfolgs therapeutischer Strategien darstellen.

Abstract

Mechanisms leading to the development of epilepsy as well as pharmacoresistance are still insufficiently understood and animal models remain essential to investigate the underlying pathologies. Positron emission tomography (PET) is a nuclear medical method allowing the visualization of neurobiological processes and hereby represents a valuable tool in clinical and preclinical epilepsy research. Meanwhile, the specific development of small animal PET scanners enables comprehensive longitudinal studies in rat and mouse epilepsy models for the whole process of epileptogenesis. Although possibilities for molecule labeling are theoretically unlimited, 2-[18F]-fluoro-2-deoxy-D-glucose ([18F]FDG), which serves as a marker of cellular glucose consumption, is the PET tracer predominantly used in epilepsy research to date. Development and preclinical evaluation of new PET tracers, which might serve as biomarkers for epileptogenesis or seizure-associated processes will be in focus of forthcoming research efforts. Moreover, such biomarkers can be suitable means for monitoring the success of therapeutic strategies in animal models and human patients.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Abb. 1
Abb. 2
Abb. 3
Abb. 4
Abb. 5

Literatur

  1. Bankstahl JP, Bankstahl M, Kuntner C et al (2011) A novel positron emission tomography imaging protocol identifies seizure-induced regional overactivity of P-glycoprotein at the blood-brain barrier. J Neurosci 31:8803–8811

    Article  PubMed  CAS  Google Scholar 

  2. Bankstahl JP, Kuntner C, Abrahim A et al (2008) Tariquidar-induced P-glycoprotein inhibition at the rat blood-brain barrier studied with (R)-C-11-verapamil and PET. J Nucl Med 49:1328–1335

    Article  PubMed  CAS  Google Scholar 

  3. Bartmann H, Fuest C, La Fougère C et al (2010) Imaging of P-glycoprotein-mediated pharmacoresistance in the hippocampus: proof-of-concept in a chronic rat model of temporal lobe epilepsy. Epilepsia 51:1780–1790

    Article  PubMed  CAS  Google Scholar 

  4. Bialer M, White HS (2010) Key factors in the discovery and development of new antiepileptic drugs. Nature Reviews Drug Discovery 9:68–82

    Article  PubMed  CAS  Google Scholar 

  5. Dedeurwaerdere S, Cornelissen B, Van Laere K et al (2005) Small animal positron emission tomography during vagus nerve stimulation in rats: a pilot study. Epilepsy Res 67:133–141

    Article  PubMed  Google Scholar 

  6. Froklage F, Syvänen S, Hendrikse N et al (2010) Effect of P-glycoprotein function on cerebral uptake of the GABAA-receptor ligand [11C]flumazenil in rats and mice. Proceedings of the 64th Annual Meeting of the American Epilepsy Society:A3161

    Google Scholar 

  7. Gao F, Guo Y, Zhang H et al (2009) Anterior thalamic nucleus stimulation modulates regional cerebral metabolism: an FDG-MicroPET study in rats. Neurobiol Dis 34:477–483

    Article  PubMed  CAS  Google Scholar 

  8. Goffin K, Bormans G, Casteels C et al (2008) An in vivo [F-18]MK-9470 microPET study of type 1 cannabinoid receptor binding in Wistar rats after chronic administration of valproate and levetiracetam. Neuropharmacology 54:1103–1106

    Article  PubMed  CAS  Google Scholar 

  9. Goffin K, Dedeurwaerdere S, Van Laere K et al (2008) Neuronuclear assessment of patients with epilepsy. Semin Nucl Med 38:227–239

    Article  PubMed  Google Scholar 

  10. Goffin K, Van Paesschen W, Dupont P et al (2009) Longitudinal microPET imaging of brain glucose metabolism in rat lithium-pilocarpine model of epilepsy. Exp Neurol 217:205–209

    Article  PubMed  CAS  Google Scholar 

  11. Guo Y, Gao F, Wang S et al (2009) In vivo mapping of temporospacial changes in glucose utilization in rat brain during epileptogenesis: an [18F]-fluorodeoxyglucose-small animal positron emission tomography study. Neuroscience 162:972–979

    Article  PubMed  CAS  Google Scholar 

  12. Jupp B, Williams J, Binns D et al (2007) Imaging small animal models of epileptogenesis. Neurology Asia 12:51–54

    Google Scholar 

  13. Kornblum HI, Araujo DM, Annala AJ et al (2000) In vivo imaging of neuronal activation and plasticity in the rat brain by high resolution positron emission tomography (microPET). Nat Biotechnol 18:655–660

    Article  PubMed  CAS  Google Scholar 

  14. Kuntner C, Bankstahl JP, Bankstahl M et al (2010) Dose-response assessment of tariquidar and elacridar and regional quantification of P-glycoprotein inhibition at the rat blood-brain barrier using (R)-[11C]verapamil PET. Eur J Nucl Med Mol Imaging 37:942–953

    Article  PubMed  CAS  Google Scholar 

  15. La Fougère C, Boning G, Bartmann H et al (2010) Uptake and binding of the serotonin 5-HT1A antagonist [18F]-MPPF in brain of rats: effects of the novel P-glycoprotein inhibitor tariquidar. Neuroimage 49:1406–1415

    Article  Google Scholar 

  16. Labots M, Verbeek J, Eriksson J et al (2011) (11)C Phenytoin is a weak P-glycoprotein substrate in rat – Initial PET studies. J Labelled Comp Radiopharm 54:286–286

    Google Scholar 

  17. Lee EM, Park GY, Im KC et al (2012) Changes in glucose metabolism and metabolites during the epileptogenic process in the lithium-pilocarpine model of epilepsy. Epilepsia 53:860–869

    Article  PubMed  CAS  Google Scholar 

  18. Liefaard LC, Ploeger BA, Molthoff CFM et al (2005) Population pharmacokinetic analysis for simultaneous determination of B-max and K-D in vivo by positron emission tomography. Mol Imaging Biol 7:411–421

    Article  PubMed  Google Scholar 

  19. Liefaard LC, Ploeger BA, Molthoff CFM et al (2009) Changes in GABA(A) receptor properties in amygdala kindled animals: in vivo studies using [C-11]flumazenil and positron emission tomography. Epilepsia 50:88–98

    Article  PubMed  CAS  Google Scholar 

  20. Löscher W (2011) Critical review of current animal models of seizures and epilepsy used in the discovery and development of new antiepileptic drugs. Seizure Eur J Epilep 20:359–368

    Google Scholar 

  21. Löscher W, Brandt C (2010) Prevention or modification of epileptogenesis after brain insults: experimental approaches and translational research. Pharmacol Rev 62:668–700

    Article  PubMed  Google Scholar 

  22. Löscher W, Langer O (2010) Imaging of P-glycoprotein function and expression to elucidate mechanisms of pharmacoresistance in epilepsy. Curr Top Med Chem 10:1785–1791

    Article  PubMed  Google Scholar 

  23. Luurtsema G, Lubberink M, Schuit R et al (2007) Functional P-glycoprotein in the blood-brain barrier of the post status epilepticus rat: measurement using (R)-[C-11]verapamil and PET. J Cereb Blood Flow Metab 27:BP22–01H

    Google Scholar 

  24. Mairinger S, Bankstahl JP, Kuntner C et al (2012) The antiepileptic drug mephobarbital is not transported by P-glycoprotein or multidrug resistance protein 1 at the blood-brain barrier: a positron emission tomography study. Epilepsy Res, In Press:http://dx.doi.org/10.1016/j.eplepsyres.2012.1001.1012

  25. Matsumura A, Mizokawa S, Tanaka M et al (2003) Assessment of microPET performance in analyzing the rat brain under different types of anesthesia: comparison between quantitative data obtained with microPET and ex vivo autoradiography. Neuroimage 20:2040–2050

    Article  PubMed  Google Scholar 

  26. Mirrione MM, Konomos DK, Gravanis I et al (2010) Microglial ablation and lipopolysaccharide preconditioning affects pilocarpine-induced seizures in mice. Neurobiol Dis 39:85–97

    Article  PubMed  CAS  Google Scholar 

  27. Mirrione MM, Schiffer WK, Fowler JS et al (2007) A novel approach for imaging brain-behavior relationships in mice reveals unexpected metabolic patterns during seizures in the absence of tissue plasminogen activator. Neuroimage 38:34–42

    Article  PubMed  Google Scholar 

  28. Mirrione MM, Schiffer WK, Siddiq M et al (2006) PET imaging of glucose metabolism in a mouse model of temporal lobe epilepsy. Synapse 59:119–121

    Article  PubMed  CAS  Google Scholar 

  29. Pifferi F, Tremblay S, Plourde M et al (2008) Ketones and brain function: possible link to polyunsaturated fatty acids and availability of a new brain PET tracer, C-11-acetoacetate. Epilepsia 49:76–79

    Article  PubMed  CAS  Google Scholar 

  30. Syvänen S, Luurtsema G, Molthoff C et al (2011) (R)-[11C]Verapamil PET studies to assess changes in P-glycoprotein expression and functionality in rat blood-brain barrier after exposure to kainate-induced status epilepticus. BMC Med Imaging 11:1

    PubMed  Google Scholar 

  31. Van Vliet EA, Da Costa AS, Redeker S et al (2007) Blood-brain barrier leakage may lead to progression of temporal lobe epilepsy. Brain 130:521–534

    Article  Google Scholar 

  32. Volk HA, Löscher W (2005) Multidrug resistance in epilepsy: rats with drug-resistant seizures exhibit enhanced brain expression of P-glycoprotein compared with rats with drug-responsive seizures. Brain 128:1358–1368

    Article  PubMed  Google Scholar 

  33. Wang D, Pascual JM, Yang H et al (2006) A mouse model for Glut-1 haploinsufficiency. Hum Mol Genet 15:1169–1179

    Article  PubMed  CAS  Google Scholar 

  34. Yakushev IY, Dupont E, Buchholz H-G et al (2010) In vivo imaging of dopamine receptors in a model of temporal lobe epilepsy. Epilepsia 51:415–422

    Article  PubMed  Google Scholar 

Download references

Interessenkonflikt

Die korrespondierende Autorin gibt für sich und ihren Koautor an, dass kein Interessenkonflikt besteht.

Author information

Authors and Affiliations

  1. Präklinische Molekulare Bildgebung, Klinik für Nuklearmedizin, Medizinische Hochschule Hannover, Hannover, Deutschland

    J.P. Bankstahl

  2. Institut für Pharmakologie, Toxikologie und Pharmazie, Tierärztliche Hochschule Hannover, Bünteweg 17, 30559, Hannover, Deutschland

    M. Bankstahl

Authors
  1. J.P. Bankstahl
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. M. Bankstahl
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to M. Bankstahl.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Bankstahl, J., Bankstahl, M. Präklinische Positronen-Emissions-Tomographie-Studien in Epilepsiemodellen. Z. Epileptol. 25, 200–207 (2012). https://doi.org/10.1007/s10309-012-0260-8

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10309-012-0260-8

Schlüsselwörter

Keywords

Search

Navigation