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PET imaging of neuroinflammation in a rat traumatic brain injury model with radiolabeled TSPO ligand DPA-714

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European Journal of Nuclear Medicine and Molecular Imaging Aims and scope Submit manuscript

Abstract

Purpose

The inflammatory response in injured brain parenchyma after traumatic brain injury (TBI) is crucial in the pathological process. In order to follow microglia activation and neuroinflammation after TBI, we performed PET imaging in a rat model of TBI using 18F-labeled DPA-714, a ligand of the 18-kDa translocator protein (TSPO).

Methods

TBI was induced in male SD rats by a controlled cortical impact. The success of the TBI model was confirmed by MRI. [18F]DPA-714 was synthesized using a slightly modified TRACERLab FX-FN module and an automated procedure. In vivo PET imaging was performed at different time points after surgery using an Inveon small-animal PET scanner. The specificity of [18F]DPA-714 was confirmed by a displacement study with an unlabeled competitive TSPO ligand, PK11195. Ex vivo autoradiography as well as immunofluorescence staining was carried out to confirm the in vivo PET results.

Results

Both in vivo T2-weighted MR images and ex vivo TTC staining results revealed successful establishment of the TBI model. Compared with the sham-treated group, [18F]DPA-714 uptake was significantly higher in the injured brain area on PET images. Increased lesion-to-normal ratios of [18F]DPA-714 were observed in the brain of TBI rats on day 2 after surgery. Ratios peaked around day 6 (2.65 ± 0.36) and then decreased gradually to nearly normal levels on day 28. The displacement study using PK11195 confirmed the specific binding of [18F]DPA-714 to TSPO. The results of ex vivo autoradiography were consistent with in vivo PET results. Immunofluorescence staining showed the time course of TSPO expression after TBI and the temporal and the spatial distribution of microglia in the damaged brain area.

Conclusion

TSPO-targeted PET using [18F]DPA-714 as the imaging probe can be used to dynamically monitor the inflammatory response after TBI in a noninvasive manner. This method will not only facilitate a better understanding of the inflammatory process after TBI, but also provide a useful in vivo monitoring strategy for antiinflammation therapy of TBI.

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References

  1. Langlois JA, Rutland-Brown W, Wald MM. The epidemiology and impact of traumatic brain injury: a brief overview. J Head Trauma Rehabil. 2006;21:375–8.

    Article  PubMed  Google Scholar 

  2. Kumar A, Loane DJ. Neuroinflammation after traumatic brain injury: opportunities for therapeutic intervention. Brain Behav Immun. 2012;26:1191–201.

    Article  PubMed  Google Scholar 

  3. Ceulemans AG, Zgavc T, Kooijman R, Hachimi-Idrissi S, Sarre S, Michotte Y. The dual role of the neuroinflammatory response after ischemic stroke: modulatory effects of hypothermia. J Neuroinflammation. 2010;7:74.

    Article  PubMed Central  PubMed  Google Scholar 

  4. Block ML, Zecca L, Hong JS. Microglia-mediated neurotoxicity: uncovering the molecular mechanisms. Nat Rev Neurosci. 2007;8:57–69.

    Article  CAS  PubMed  Google Scholar 

  5. Davalos D, Grutzendler J, Yang G, Kim JV, Zuo Y, Jung S, et al. ATP mediates rapid microglial response to local brain injury in vivo. Nat Neurosci. 2005;8:752–8.

    Article  CAS  PubMed  Google Scholar 

  6. Saijo K, Glass CK. Microglial cell origin and phenotypes in health and disease. Nat Rev Immunol. 2011;11:775–87.

    Article  CAS  PubMed  Google Scholar 

  7. Gonzalez-Scarano F, Baltuch G. Microglia as mediators of inflammatory and degenerative diseases. Annu Rev Neurosci. 1999;22:219–40.

    Article  CAS  PubMed  Google Scholar 

  8. Winkeler A, Boisgard R, Awde AR, Dubois A, Theze B, Zheng J, et al. The translocator protein ligand [18F]DPA-714 images glioma and activated microglia in vivo. Eur J Nucl Med Mol Imaging. 2012;39:811–23.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  9. Martin A, Boisgard R, Theze B, Van Camp N, Kuhnast B, Damont A, et al. Evaluation of the PBR/TSPO radioligand [18F]DPA-714 in a rat model of focal cerebral ischemia. J Cereb Blood Flow Metab. 2010;30:230–41.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  10. Ji B, Maeda J, Sawada M, Ono M, Okauchi T, Inaji M, et al. Imaging of peripheral benzodiazepine receptor expression as biomarkers of detrimental versus beneficial glial responses in mouse models of Alzheimer’s and other CNS pathologies. J Neurosci. 2008;28:12255–67.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  11. Scarf AM, Kassiou M. The translocator protein. J Nucl Med. 2011;52:677–80.

    Article  CAS  PubMed  Google Scholar 

  12. Folkersma H, Foster Dingley JC, van Berckel BN, Rozemuller A, Boellaard R, Huisman MC, et al. Increased cerebral (R)-[11C]PK11195 uptake and glutamate release in a rat model of traumatic brain injury: a longitudinal pilot study. J Neuroinflammation. 2011;8:67.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  13. Yu I, Inaji M, Maeda J, Okauchi T, Nariai T, Ohno K, et al. Glial cell-mediated deterioration and repair of the nervous system after traumatic brain injury in a rat model as assessed by positron emission tomography. J Neurotrauma. 2010;27:1463–75.

    Article  PubMed  Google Scholar 

  14. Venneti S, Lopresti BJ, Wang G, Slagel SL, Mason NS, Mathis CA, et al. A comparison of the high-affinity peripheral benzodiazepine receptor ligands DAA1106 and (R)-PK11195 in rat models of neuroinflammation: implications for PET imaging of microglial activation. J Neurochem. 2007;102:2118–31.

    Article  CAS  PubMed  Google Scholar 

  15. Raghavendra Rao VL, Dogan A, Bowen KK, Dempsey RJ. Traumatic brain injury leads to increased expression of peripheral-type benzodiazepine receptors, neuronal death, and activation of astrocytes and microglia in rat thalamus. Exp Neurol. 2000;161:102–14.

    Article  CAS  PubMed  Google Scholar 

  16. Chauveau F, Van Camp N, Dolle F, Kuhnast B, Hinnen F, Damont A, et al. Comparative evaluation of the translocator protein radioligands 11C-DPA-713, 18F-DPA-714, and 11C-PK11195 in a rat model of acute neuroinflammation. J Nucl Med. 2009;50:468–76.

    Article  CAS  PubMed  Google Scholar 

  17. Doorduin J, Klein HC, Dierckx RA, James M, Kassiou M, de Vries EF. [11C]-DPA-713 and [18F]-DPA-714 as new PET tracers for TSPO: a comparison with [11C]-(R)-PK11195 in a rat model of herpes encephalitis. Mol Imaging Biol. 2009;11:386–98.

    Article  PubMed Central  PubMed  Google Scholar 

  18. Arlicot N, Vercouillie J, Ribeiro MJ, Tauber C, Venel Y, Baulieu JL, et al. Initial evaluation in healthy humans of [18F]DPA-714, a potential PET biomarker for neuroinflammation. Nucl Med Biol. 2012;39:570–8.

    Article  CAS  PubMed  Google Scholar 

  19. Guide for the Care and Use of Laboratory Animals. Washington, DC: National Academy Press; 2010.

  20. Baskaya MK, Dogan A, Temiz C, Dempsey RJ. Application of 2,3,5-triphenyltetrazolium chloride staining to evaluate injury volume after controlled cortical impact brain injury: role of brain edema in evolution of injury volume. J Neurotrauma. 2000;17:93–9.

    Article  CAS  PubMed  Google Scholar 

  21. Boutin H, Prenant C, Maroy R, Galea J, Greenhalgh AD, Smigova A, et al. [18F]DPA-714: direct comparison with [11C]PK11195 in a model of cerebral ischemia in rats. PLoS One. 2013;8:e56441.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  22. Cai W, Guzman R, Hsu AR, Wang H, Chen K, Sun G, et al. Positron emission tomography imaging of poststroke angiogenesis. Stroke. 2009;40:270–7.

    Article  PubMed  Google Scholar 

  23. Radu CG, Shu CJ, Shelly SM, Phelps ME, Witte ON. Positron emission tomography with computed tomography imaging of neuroinflammation in experimental autoimmune encephalomyelitis. Proc Natl Acad Sci U S A. 2007;104:1937–42.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  24. Chen DL, Schuster DP. Positron emission tomography with [18F]fluorodeoxyglucose to evaluate neutrophil kinetics during acute lung injury. Am J Physiol Lung Cell Mol Physiol. 2004;286:L834–40.

    Article  CAS  PubMed  Google Scholar 

  25. Tardy M, Fages C, Le Prince G, Rolland B, Nunez J. Regulation of the glial fibrillary acidic protein (GFAP) and of its encoding mRNA in the developing brain and in cultured astrocytes. Adv Exp Med Biol. 1990;265:41–52.

    Article  CAS  PubMed  Google Scholar 

  26. Galan X, Llobera M, Ramirez I. Lipoprotein lipase in developing rat tissues: differences between Wistar and Sprague–Dawley rats. Biol Neonate. 1993;64:295–303.

    Article  CAS  PubMed  Google Scholar 

  27. James ML, Fulton RR, Vercoullie J, Henderson DJ, Garreau L, Chalon S, et al. DPA-714, a new translocator protein-specific ligand: synthesis, radiofluorination, and pharmacologic characterization. J Nucl Med. 2008;49:814–22.

    Article  CAS  PubMed  Google Scholar 

  28. Kuhnast B, Damont A, Hinnen F, Catarina T, Demphel S, Le Helleix S, et al. [18F]DPA-714, [18F]PBR111 and [18F]FEDAA1106-selective radioligands for imaging TSPO 18 kDa with PET: automated radiosynthesis on a TRACERLAb FX-FN synthesizer and quality controls. Appl Radiat Isot. 2012;70:489–97.

    Article  CAS  PubMed  Google Scholar 

  29. James ML, Selleri S, Kassiou M. Development of ligands for the peripheral benzodiazepine receptor. Curr Med Chem. 2006;13:1991–2001.

    Article  CAS  PubMed  Google Scholar 

  30. Shlosberg D, Benifla M, Kaufer D, Friedman A. Blood–brain barrier breakdown as a therapeutic target in traumatic brain injury. Nat Rev Neurol. 2010;6:393–403.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  31. Chen MK, Baidoo K, Verina T, Guilarte TR. Peripheral benzodiazepine receptor imaging in CNS demyelination: functional implications of anatomical and cellular localization. Brain. 2004;127:1379–92.

    Article  PubMed  Google Scholar 

  32. Schilling M, Besselmann M, Muller M, Strecker JK, Ringelstein EB, Kiefer R. Predominant phagocytic activity of resident microglia over hematogenous macrophages following transient focal cerebral ischemia: an investigation using green fluorescent protein transgenic bone marrow chimeric mice. Exp Neurol. 2005;196:290–7.

    Article  CAS  PubMed  Google Scholar 

  33. Venneti S, Lopresti BJ, Wang G, Hamilton RL, Mathis CA, Klunk WE, et al. PK11195 labels activated microglia in Alzheimer’s disease and in vivo in a mouse model using PET. Neurobiol Aging. 2009;30:1217–26.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  34. 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  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This work was supported by the National Basic Research Program of China (973 program, 2013CB733803, 2013CB733802), and the Intramural Research Program (IRP) of the National Institute of Biomedical Imaging and Bioengineering (NIBIB), National Institutes of Health (NIH).

Conflicts of interest

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Author information

Authors and Affiliations

  1. Jiangsu Key Laboratory of Molecular Imaging and Functional Imaging, Department of Radiology, Zhongda Hospital, Medical School of Southeast University, Nanjing, 210009, China

    Yu Wang & Gaojun Teng

  2. Laboratory of Molecular Imaging and Nanomedicine (LOMIN), National Institute of Biomedical Imaging and Bioengineering (NIBIB), National Institutes of Health (NIH), Bethesda, MD, 20892, USA

    Yu Wang, Xuyi Yue, Dale O. Kiesewetter, Gang Niu & Xiaoyuan Chen

  3. 9 Memorial Drive, 9/1 W111, Bethesda, MD, 20892, USA

    Gang Niu

  4. 87 Dingjiaqiao Road, Nanjing, Jiangsu, China, 210009

    Gaojun Teng

  5. 31 Center Drive, Suite 1C14, Bethesda, MD, 20892-2281, USA

    Xiaoyuan Chen

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  1. Yu Wang
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  2. Xuyi Yue
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Correspondence to Gang Niu, Gaojun Teng or Xiaoyuan Chen.

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Wang, Y., Yue, X., Kiesewetter, D.O. et al. PET imaging of neuroinflammation in a rat traumatic brain injury model with radiolabeled TSPO ligand DPA-714. Eur J Nucl Med Mol Imaging 41, 1440–1449 (2014). https://doi.org/10.1007/s00259-014-2727-5

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  • DOI: https://doi.org/10.1007/s00259-014-2727-5

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