Skip to main content

Advertisement

SpringerLink
Log in

Two activated stages of microglia and PET imaging of peripheral benzodiazepine receptors with [11C]PK11195 in rats

  • Original Article
  • Published:
Annals of Nuclear Medicine Aims and scope Submit manuscript

Abstract

Objective

The transition of microglia from the normal resting state to the activated state is associated with an increased expression of peripheral benzodiazepine receptors (PBR). The extent of PBR expression is dependent on the level of microglial activation. A PBR ligand, [11C]PK11195, has been used for imaging of the activation of microglia in vivo. We evaluated whether [11C]PK11195 PET can indicate differences of microglial activation between no treatment and lipopolysaccharide (LPS) treatment in a rat artificial injury model of brain inflammation.

Methods

On day 1, a small aliquot of absolute ethanol was injected into the rat right striatum (ST) to produce artificial brain injury. On day 3, MRI scans were performed to evaluate and select rats showing a similar degree of brain injury. Then LPS or vehicle was administered intraperitoneally. On day 4, PET scans were performed after a bolus injection of [11C]PK11195. Eleven rats (7 LPS administered rats, 4 LPS non-administered rats) were evaluated. We used uptake ratios of the integral of right and left striatum from 0 to 60 min as an estimate of PBR distribution volume (V 60). The number of activated microglia and mRNA expression of inflammatory cytokines (TNFα, IL-1β) were assessed by isolectin-B4 staining and RT-PCR, respectively.

Results

Right/left ST V 60 ratios of LPS group were significantly higher than those of non-LPS group (P < 0.03). Although there were no significant differences in the number of activated microglia between the two groups, LPS group showed higher expression of inflammatory cytokines (TNFα, IL-1β) than the non-treated group indicating that further activation was induced by LPS treatment.

Conclusion

The results suggest that intensity of PBR signals in [11C]PK11195 PET may be related to the level of microglial activation rather than the number in activated microglia at least in an artificial brain injury model.

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. Kreutzberg GW. Microglia: a sensor for pathological events in the CNS. Trends Neurosci. 1996;19:312–8.

    Article  PubMed  CAS  Google Scholar 

  2. Banati RB. Neuropathological imaging: in vivo detection of glial activation as a measure of disease and adaptive change in the brain. Br Med Bull. 2003;65:121–31.

    Article  PubMed  Google Scholar 

  3. Takeuchi A, Isobe K, Miyaishi O, Sawada M, Fan ZH, Nakashima I, et al. Microglial NO induces delayed neuronal death following acute injury in the striatum. Eur J Neurosci. 1998;10:1613–20.

    Article  PubMed  CAS  Google Scholar 

  4. Sawada M, Suzumura A, Marunouchi T. Cytokine network in the central nervous system and its roles in growth and differentiation of glial and neuronal cells. Int J Dev Neurosci. 1995;13:253–64.

    Article  PubMed  CAS  Google Scholar 

  5. Sawada M, Sawada H, Nagatsu T. Effects of aging on neuroprotective and neurotoxic properties of microglia in neurodegenerative diseases. Neurodegener Dis. 2008;5:254–6.

    Article  PubMed  CAS  Google Scholar 

  6. Banati RB, Egensperger R, Maassen A, Hager G, Kreutzberg G, Graeber MB. Mitochondria in activated microglia in vitro. J Neurocytol. 2004;33:535–41.

    Article  PubMed  Google Scholar 

  7. Papadopoulos V, Baraldi M, Guilarte TR, Knudsen TB, Lacapere JJ, Lindemann P, et al. Translocator protein (18 kDa): new nomenclature for the peripheral-type benzodiazepine receptor based on its structure and molecular function. Trends Pharmacol Sci. 2006;27:402–9.

    Article  PubMed  CAS  Google Scholar 

  8. Vowinckel E, Reutens D, Becher B, Verge G, Evans A, Owens T, et al. PK11195 binding to the peripheral benzodiazepine receptor as a marker of microglia activation in multiple sclerosis and experimental autoimmune encephalomyelitis. J Neurosci Res. 1997;50:345–53.

    Article  PubMed  CAS  Google Scholar 

  9. Debruyne JC, VanLaere KJ, Versijpt J, DeVos F, Eng JK, Strijckmans K, et al. Semiquantification of the peripheral-type benzodiazepine ligand [11C]PK11195 in normal human brain and application in multiple sclerosis patients. Acta Neurol Belg. 2002;102:127–35.

    PubMed  Google Scholar 

  10. Zhang MR, Maeda J, Ogawa M, Noguchi J, Ito T, Obayashi S, et al. Development of a new radioligand, N-(5-fluoro-2-phenoxyphenyl)-N-(2-[18F]fluoroethyl-5-methoxybenzyl) acetamide, for PET imaging of peripheral benzodiazepine receptor in primate brain. J Med Chem. 2004;47:2228–35.

    Article  PubMed  CAS  Google Scholar 

  11. Groom GN, Junck L, Foster NL, Frey KA, Kuhl DE. PET of peripheral benzodiazepine binding sites in the microgliosis of Alzheimer’s disease. J Nucl Med. 1995;36:2207–10.

    PubMed  CAS  Google Scholar 

  12. Maeda J, Higuchi M, Inaji M, Ji B, Haneda E, Okauchi T, et al. Phase-dependent roles of reactive microglia and astrocytes in nervous system injury as delineated by imaging of peripheral benzodiazepine receptor. Brain Res. 2007;1157:100–11.

    Article  PubMed  CAS  Google Scholar 

  13. Venneti S, Lopresti BJ, Wang G, Slagel SL, Mason NS, Mathis C, et al. A comparison of the high-affinity peripheral benzodiazepine receptor ligands DAA 1106 and (R)-PK11195 in rat models of neuroinflammation: implications for PET imaging of microglial activation. J Neurochem. 2007;102:2118–31.

    Article  PubMed  CAS  Google Scholar 

  14. Imaizumi M, Kim H-J, Zoghbi SS, Briard E, Hong J, Musachio JL, et al. PET imaging with [11C]PBR28 can localize and quantify upregulated peripheral benzodiazepine receptors associated with cerebral ischemia in rat. Neurosci Lett. 2007;411:200–5.

    Article  PubMed  CAS  Google Scholar 

  15. Toyama H, Hatano K, Suzuki H, Ichise M, Momosaki S, Kudo G, et al. In vivo imaging of microglial activation using a peripheral benzodiazepine receptor ligand: [11C]PK-11195 and animal PET following ethanol injury in rat striatum. Ann Nucl Med. 2008;22:417–24.

    Article  PubMed  Google Scholar 

  16. Sakiyama Y, Hatano K, Kato T, Tajima T, Kawasumi Y, Ito K. Stimulation of adenosine A1 receptors decreases in vivo dopamine D1 receptor binding of [11C]SCH23390 in the cat striatum revealed by positron emission tomography. Ann Nucl Med. 2007;21:447–53.

    Article  PubMed  CAS  Google Scholar 

  17. Banati RB. Visualizing microglial activation in vivo. Glia. 2002;40:206–17.

    Article  PubMed  Google Scholar 

  18. Cagnin A, Brooks DJ, Kennedy AM, Gunn RN, Myers R, Turkheimer FE, et al. In vivo measurement of activated microglia in dementia. Lancet. 2001;358:461–7.

    Article  PubMed  CAS  Google Scholar 

  19. Gunn RN, Lammertsma AA, Hume SP, Cunningham VJ. Parametric imaging of ligand-receptor interactions using a reference tissue model and cluster analysis. In: Carson R, Daule M, Witherspoon P, Herscovitch P, editors. Quantitative functional brain imaging with positron emission tomography. San Diego: Academic Press; 1998. p. 401–6.

    Chapter  Google Scholar 

  20. Kropholler MA, Boellaard R, Schuitemaker A, Folkersma H, van Berckel BNM, Lammertsma A. Evaluation of reference tissue models for the analysis of [11C](R)-PK11195 studies. J Cereb Blood Flow Metab. 2006;26:1431–41.

    Article  PubMed  CAS  Google Scholar 

  21. Schuitemaker A, van Berckel BNM, Kropholler MA, Veltman DJ, Scheltens P, Jonker C, et al. SPM analysis of parametric (R)-[11C]-PK11195 binding images: plasma input versus reference tissue parametric methods. NeuroImage. 2007;35:1473–9.

    Article  PubMed  Google Scholar 

  22. Lassen NA. Neuroreceptor quantitation in vivo by the steadystate principle using constant infusion or bolus injection of radioactive tracers. J Cereb Blood Flow Metab. 1992;12:709–16.

    PubMed  CAS  Google Scholar 

  23. Streit WJ. An improved staining method for rat microglial cells using the lectin from Griffonia simplicifonia (GSA I-B4). J Histochem Cytochem. 1990;38:1683–6.

    PubMed  CAS  Google Scholar 

  24. Suradhat S, Thanawongnuwech R, Poovorawan Y. Upregulation of IL-10 gene expression in porcine peripheral blood mononuclear cells by porcine reproductive and respiratory syndrome virus. J Gen Virol. 2003;84:453–9.

    Article  PubMed  CAS  Google Scholar 

  25. Hardwick MJ, Chen MK, Baidoo K, Pomper MG, Guilarte TR. In vivo imaging of PBRs in mouse lungs: a biomarker of inflammation. Mol Imaging. 2005;4:432–8.

    PubMed  Google Scholar 

  26. Venneti S, Wang G, Wiley CA. Activated macrophages in HIV encephalitis and a macaque model show increased [3H](R)-PK11195 binding in a PI3-kinase-dependent manner. Neurosci Lett. 2007;426:117–22.

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

We would like to thank Mr. Junichiro Abe, Department of Brain Science and Molecular Imaging, National Institute for Longevity Sciences, National Center for Geriatrics and Gerontology, Obu, Japan for running cyclotron. We appreciate radiological technologists, Fujita Health University Hospital for running the MRI scanner. We also thank Eizou Umezawa, PhD, School of Health Sciences, Fujita Health University for providing support with regard to statistical analysis. This study was supported by Japan Society for the Promotion of Science (JSPS) KAKENHI (18591369, 80001800), the 21st Century COE (Center of Excellence) Medical Program (Development Center for Targeted and Minimally Invasive Diagnosis and Treatment) from JSPS, and a grant from Fujita Health University.

Author information

Authors and Affiliations

  1. Department of Radiology, Fujita Health University, 1-98 Dengakugakubo, Kutsukake, Toyoake, Aichi, 470-1192, Japan

    Fumitaka Ito, Hiroshi Toyama, Gen Kudo & Kazuhiro Katada

  2. Department of Brain Function, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Japan

    Hiromi Suzuki & Makoto Sawada

  3. Department of Brain Science and Molecular Imaging, National Institute for Longevity Science, National Center for Geriatrics and Gerontology, Obu, Japan

    Kentaro Hatano & Kengo Ito

  4. Department of Radiology, Columbia University, New York, NY, USA

    Masanori Ichise

Authors
  1. Fumitaka Ito
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Hiroshi Toyama
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Gen Kudo
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Hiromi Suzuki
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Kentaro Hatano
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Masanori Ichise
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Kazuhiro Katada
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Kengo Ito
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Makoto Sawada
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Fumitaka Ito.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Ito, F., Toyama, H., Kudo, G. et al. Two activated stages of microglia and PET imaging of peripheral benzodiazepine receptors with [11C]PK11195 in rats. Ann Nucl Med 24, 163–169 (2010). https://doi.org/10.1007/s12149-009-0339-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12149-009-0339-0

Keywords

Search

Navigation