Skip to main content
SpringerLink
Log in

[18F]FDG PET Neuroimaging Predicts Pentylenetetrazole (PTZ) Kindling Outcome in Rats

  • Research Article
  • Published:
Molecular Imaging and Biology Aims and scope Submit manuscript

Abstract

Purpose

Epileptogenesis, i.e., development of epilepsy, involves a number of processes that alter the brain function in the way that triggers spontaneous seizures. Kindling is one of the most used animal models of temporal lobe epilepsy (TLE) and epileptogenesis, although chemical kindling suffers from high inter-assay success unpredictability. This study was aimed to analyze the eventual regional brain metabolic changes during epileptogenesis in the pentylenetetrazole (PTZ) kindling model in order to obtain a predictive kindling outcome parameter.

Procedures

In vivo longitudinal positron emission tomography (PET) scans with 2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG) along the PTZ kindling protocol (35 mg/kg intraperitoneally (i.p.), 18 sessions) in adult male rats were performed in order to evaluate the regional brain metabolism.

Results

The half of the PTZ-injected rats reached the kindled state. In addition, a significant decrease of [18F]FDG uptake at the end of the protocol in most of the brain structures of kindled animals was found, reflecting the characteristic epilepsy-associated hypometabolism. However, PTZ-injected animals but not reaching the kindled state did not show this widespread brain hypometabolism. Retrospective analysis of the data revealed that hippocampal [18F]FDG uptake normalized to pons turned out to be a predictive index of the kindling outcome. Thus, a 19.06 % reduction (p = 0.008) of the above parameter was found in positively kindled rats compared to non-kindled ones just after the fifth PTZ session.

Conclusion

Non-invasive PET neuroimaging was a useful tool for discerning epileptogenesis progression in this animal model. Particularly, the [18F]FDG uptake of the hippocampus proved to be an early predictive parameter to differentiate resistant and non-resistant animals to the PTZ kindling.

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

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Akhlaghi Z, Sayyah M, Mokhtari M, Ahmadi A (2012) Effect of intra-amygdala injection of lipopolysaccharide on kindling epileptogenesis in adult rats. Arch Iran Med 15:557–559

    CAS  PubMed  Google Scholar 

  2. Engel JJ (2001) Intractable epilepsy: definition and neurobiology. Epilepsia 42(Suppl 6):3

    Article  PubMed  Google Scholar 

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

    Article  PubMed  Google Scholar 

  4. Stables JP, Bertram EH, White HS et al (2002) Models for epilepsy and epileptogenesis: report from the NIH workshop, Bethesda, Maryland. Epilepsia 43:1410–1420

    Article  PubMed  Google Scholar 

  5. Löscher W (2002) Animal models of epilepsy for the development of antiepileptogenic and disease-modifying drugs. A comparison of the pharmacology of kindling and post-status epilepticus models of temporal lobe epilepsy. Epilepsy Res 50:105–123

  6. Dedeurwaerdere S, Jupp B, O’Brien TJ (2007) Positron emission tomography in basic epilepsy research: a view of the epileptic brain. Epilepsia 48:56–64

    Article  PubMed  Google Scholar 

  7. White HS (2002) Animal models of epileptogenesis. Neurology 59:S7–S14

    Article  Google Scholar 

  8. Martín E, Pozo M (2006) Animal models for the development of new neuropharmacological therapeutics in the status epilepticus. Curr Neuropharmacol 4:33–40

    Article  PubMed  PubMed Central  Google Scholar 

  9. Goddard GV, McIntyre DC, Leech CK (1969) A permanent change in brain function resulting from daily electrical stimulation. Exp Neurol 25:295–330

    Article  CAS  PubMed  Google Scholar 

  10. McIntyre DC (2006) The kindling phenomenon. In: Pitkänen A, Schwartzkroin P, Moshe SL (eds) Model. Seizures epilepsy. Elsevier Inc, Amsterdam, pp 351–363

  11. Dhir A (2012) Pentylenetetrazol (PTZ) kindling model of epilepsy. Curr Protoc Neurosci 1:1–12

    Google Scholar 

  12. Ono J, Vieth RF, Walson PD (1990) Electrocorticographical observation of seizures induced by pentylenetetrazol (PTZ) injection in rats. Funct Neurol 5:345–352

    CAS  PubMed  Google Scholar 

  13. Gilbert M, Goodman J (2006) Chemical kindling. In: Pitkänen A, Schwartzkroin P, Moshé S (eds) Model. Seizures epilepsy. Elsevier Inc, Amsterdam, pp 379–391

  14. Corda MG, Orlandi M, Lecca D et al (1991) Pentylenetetrazol-induced kindling in rats: effect of GABA function inhibitors. Pharmacol Biochem Behav 40:329–333

    Article  CAS  PubMed  Google Scholar 

  15. Ito T, Hori M, Yoshida K, Shimizu M (1977) Effect of anticonvulsants on seizures developing in the course of daily administration of pentetrazol to rats. Eur J Pharmacol 45:165–172

    Article  CAS  PubMed  Google Scholar 

  16. O’Brien TJ, Miles K, Ware R et al (2008) The cost-effective use of 18F-FDG PET in the presurgical evaluation of medically refractory focal epilepsy. J Nucl Med 49:931–937

    Article  PubMed  Google Scholar 

  17. Duncan J (2009) The current status of neuroimaging for epilepsy. Curr Opin Neurol 22:179–184

    PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  20. Zhang L, Guo Y, Hu H et al (2015) FDG-PET and NeuN-GFAP immunohistochemistry of hippocampus at different phases of the pilocarpine model of temporal lobe epilepsy. Int J Med Sci 12:288–294

    Article  PubMed  PubMed Central  Google Scholar 

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

    Google Scholar 

  22. 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  CAS  PubMed  Google Scholar 

  23. Shiha AA, de Cristóbal J, Delgado M et al (2015) Subacute administration of fluoxetine prevents short-term brain hypometabolism and reduces brain damage markers induced by the lithium-pilocarpine model of epilepsy in rats. Brain Res Bull 111:36–47

    Article  CAS  PubMed  Google Scholar 

  24. Carmody S, Brennan L (2010) Effects of pentylenetetrazole-induced seizures on metabolomic profiles of rat brain. Neurochem Int 56:340–344

    Article  CAS  PubMed  Google Scholar 

  25. Diehl RG, Smialowski A, Gotwo T (1984) Development and persistence of kindled seizures after repeated injections of pentylenetetrazol in rats and guinea pigs. Epilepsia 25:506–510

    Article  CAS  PubMed  Google Scholar 

  26. Prieto E, Collantes M, Delgado M et al (2011) Statistical parametric maps of 18F-FDG PET and 3-D autoradiography in the rat brain: a cross-validation study. Eur J Nucl Med Mol Imaging 38:2228–2237

    Article  PubMed  Google Scholar 

  27. Schiffer WK, Mirrione MM, Biegon A et al (2006) Serial microPET measures of the metabolic reaction to a microdialysis probe implant. J Neurosci Methods 155:272–284

    Article  CAS  PubMed  Google Scholar 

  28. Park GY, Lee EM, Seo M-S et al (2015) Preserved hippocampal glucose metabolism on (18)F-FDG PET after transplantation of human umbilical cord blood-derived mesenchymal stem cells in chronic epileptic rats. J Korean Med Sci 30:1232–1240

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Ono J, Walson PD (1991) Effects of injection interval on pentylenetetrazol (PTZ) kindled seizures in rats. Med J Osaka Univ 40:45–49

    CAS  PubMed  Google Scholar 

  30. Fischer W, Kittner H (1998) Influence of ethanol on the pentylenetetrazol-induced kindling in rats. J Neural Transm 105:1129–1142

    Article  CAS  PubMed  Google Scholar 

  31. Fang F, Lei H (2010) Increased hippocampal T2 in a rat model of pentylenetetrazol-induced kindling correlates with seizure scores. J Neurol Sci 292:16–23

    Article  PubMed  Google Scholar 

  32. Kaya M, Gurses C, Kalayci R et al (2008) Morphological and functional changes of blood–brain barrier in kindled rats with cortical dysplasia. Brain Res 1208:181–191

    Article  CAS  PubMed  Google Scholar 

  33. Vivash L, Gregoire M-C, Lau EW et al (2013) 18F-flumazenil: a γ-aminobutyric acid A-specific PET radiotracer for the localization of drug-resistant temporal lobe epilepsy. J Nucl Med 54:1270–1277

    Article  CAS  PubMed  Google Scholar 

  34. Abadie P, Baron JC, Bisserbe JC et al (1992) Central benzodiazepine receptors in human brain: estimation of regional B max and KD values with positron emission tomography. Eur J Pharmacol 213:107–115

    Article  CAS  PubMed  Google Scholar 

  35. Abadie P, Baron JC, Bisserbe JC et al (1991) The central benzodiazepine receptor (cBZR): studies by PET. Eur Neuropsychopharmacol 1:226–229

    Article  Google Scholar 

  36. Millet P, Graf C, Buck A et al (2002) Evaluation of the reference tissue models for PET and SPECT benzodiazepine binding parameters. Neuroimage 17:928–942

    Article  PubMed  Google Scholar 

  37. Delforge J, Pappata S, Millet P et al (1995) Quantification of benzodiazepine receptors in human brain using PET, [11C]flumazenil, and a single-experiment protocol. J Cereb Blood Flow Metab 15:284–300

    Article  CAS  PubMed  Google Scholar 

  38. Jupp B, Williams J, Binns D et al (2012) Hypometabolism precedes limbic atrophy and spontaneous recurrent seizures in a rat model of TLE. Epilepsia 53:1233–1244

    Article  PubMed  Google Scholar 

  39. Virdee K, Cumming P, Caprioli D et al (2012) Applications of positron emission tomography in animal models of neurological and neuropsychiatric disorders. Neurosci Biobehav Rev 36:1188–1216

    Article  Google Scholar 

  40. Keogh BP, Cordes D, Stanberry L et al (2005) BOLD-fMRI of PTZ-induced seizures in rats. Epilepsy Res 66:75–90

    Article  CAS  PubMed  Google Scholar 

  41. Choy M, Dubé CM, Patterson K et al (2014) A novel, noninvasive, predictive epilepsy biomarker with clinical potential. J Neurosci 34:8672–8684

    Article  CAS  PubMed  Google Scholar 

  42. Jin Y, Lim C-M, Kim S-W et al (2009) Fluoxetine attenuates kainic acid-induced neuronal cell death in the mouse hippocampus. Brain Res 1281:108–116

    Article  CAS  PubMed  Google Scholar 

  43. Baracskay P, Szepesi Z, Orbán G et al (2008) Generalization of seizures parallels the formation of “dark” neurons in the hippocampus and pontine reticular formation after focal-cortical application of 4-aminopyridine (4-AP) in the rat. Brain Res 1228:217–228

    Article  CAS  PubMed  Google Scholar 

  44. Duveau V, Arthaud S, Serre H et al (2005) Transient hyperthermia protects against subsequent seizures and epilepsy-induced cell damage in the rat. Neurobiol Dis 19:142–149

    Article  PubMed  Google Scholar 

  45. O’Brien TJ, Newton MR, Cook MJ et al (1997) Hippocampal atrophy is not a major determinant of regional hypometabolism in temporal lobe epilepsy. Epilepsia 38:74–80

    Article  PubMed  Google Scholar 

  46. Fink GR, Pawlik G, Stefan H et al (1996) Temporal lobe epilepsy: evidence for interictal uncoupling of blood flow and glucose metabolism in temporomesial structures. J Neurol Sci 137:28–34

    Article  CAS  PubMed  Google Scholar 

  47. Foldvary N, Lee N, Hanson MW et al (1999) Correlation of hippocampal neuronal density and FDG-PET in mesial temporal lobe epilepsy. Epilepsia 40:26–29

    Article  CAS  PubMed  Google Scholar 

  48. Garcia-Garcia L, Shiha AA, Bascunana P et al (2015) Serotonin depletion does not modify the short-term brain hypometabolism and hippocampal neurodegeneration induced by the lithium-pilocarpine model of status epilepticus in rats. Cell Mol Neurobiol. doi:10.1007/s10571-015-0240-4

    PubMed  Google Scholar 

Download references

Acknowledgments

This work was funded by the Spanish Ministry of Science (SAF2009-09020) and Comunidad de Madrid grants (I2M2; P2010/BMD-2349). Pablo Bascuñana was financially supported by the “Alfonso Casanava” predoctoral research grant (Instituto Tecnológico PET-Universidad Complutense de Madrid).

Author information

Author notes

  1. Pablo Bascuñana

    Present address: Preclinical Molecular Imaging Unit, Department of Nuclear Medicine, Hannover Medical School, Hannover, Germany

  2. Julián Javela

    Present address: School of Psychology, Antonio Nariño University, Bogotá, Colombia

Authors and Affiliations

  1. Unidad de Cartografía Cerebral, Instituto Pluridisciplinar, Universidad Complutense de Madrid, Paseo Juan XXIII no. 1, 28040, Madrid, Spain

    Pablo Bascuñana, Julián Javela, Mercedes Delgado, Rubén Fernández de la Rosa, Ahmed Anis Shiha, Luis García-García & Miguel Ángel Pozo

  2. Departamento de Farmacología, Facultad de Farmacia, Universidad Complutense de Madrid, Plaza Ramón y Cajal s/n, 28040, Madrid, Spain

    Mercedes Delgado & Luis García-García

  3. Instituto Tecnológico PET, C/Manuel Bartolomé Cossío, 10, 28040, Madrid, Spain

    Miguel Ángel Pozo

  4. Departamento de Fisiología, Facultad de Medicina, Universidad Complutense de Madrid, Plaza Ramón y Cajal s/n, 28040, Madrid, Spain

    Miguel Ángel Pozo

Authors
  1. Pablo Bascuñana
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Julián Javela
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Mercedes Delgado
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Rubén Fernández de la Rosa
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Ahmed Anis Shiha
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Luis García-García
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Miguel Ángel Pozo
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Luis García-García.

Ethics declarations

All the procedures were performed in accordance with the guidelines of the European Union (2010/63/EU) for the use of animals for scientific purposes. This study was approved by the Ethical Animal Research Committee of the Universidad Complutense de Madrid. All efforts were made to minimize suffering and the number of animals used in this study.

Conflict of Interest

The authors declare that they have no conflict interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Bascuñana, P., Javela, J., Delgado, M. et al. [18F]FDG PET Neuroimaging Predicts Pentylenetetrazole (PTZ) Kindling Outcome in Rats. Mol Imaging Biol 18, 733–740 (2016). https://doi.org/10.1007/s11307-016-0950-0

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11307-016-0950-0

Key words

Search

Navigation