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[11C]DAC-PET for Noninvasively Monitoring Neuroinflammation and Immunosuppressive Therapy Efficacy in Rat Experimental Autoimmune Encephalomyelitis Model

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Abstract

Neuroimaging measures have potential for monitoring neuroinflammation to guide treatment before the occurrence of significant functional impairment or irreversible neuronal damage in multiple sclerosis (MS). N-Benzyl-N-methyl-2-(7-[11C]methyl-8-oxo-2-phenyl-7,8-dihydro-9H-purin-9-yl) acetamide ([11C]DAC), a new developed positron emission tomography (PET) probe for translocator protein 18 kDa (TSPO), has been adopted to evaluate the neuroinflammation and treatment effects of experimental autoimmune encephalomyelitis (EAE), an animal model of MS. [11C]DAC-PET enabled visualization of neuroinflammation lesion of EAE by tracing TSPO expression in the spinal cords; the maximal uptake value reached in day 11 and 20 EAE rats with profound inflammatory cell infiltration compared with control, day 0 and 60 EAE rats. Biodistribution studies and in vitro autoradiography confirmed these in vivo imaging results. Doubling immunohistochemical studies showed the infiltration and expansion of CD4+ T cells and CD11b+ microglia; CD68+ macrophages were responsible for the increased TSPO levels visualized by [11C]DAC-PET. Furthermore, mRNA level analysis of the cytokines by quantitative reverse-transcription polymerase chain reaction (qRT-PCR) revealed that TSPO+/CD4 T cells, TSPO+ microglia and TSPO+ macrophages in EAE spinal cords were activated and secreted multiple proinflammation cytokines to mediate inflammation lesions of EAE. EAE rats treated with an immunosuppressive agent: 2-amino-2-[2-(4-octylphenyl)ethyl] propane-1,3-diolhydrochloride (FTY720), which exhibited an absence of inflammatory cell infiltrates, displaying a faint radioactive signal compared with the high accumulation of untreated EAE rats. These results indicated that [11C] DAC-PET imaging is a sensitive tool for noninvasively monitoring the neuroinflammation response and evaluating therapeutic interventions in EAE.

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Acknowledgements

The authors are grateful to Dr. M. Higuchi for the gift of antibody NP155 and Dr. H. Kimura for his critical comments and useful suggestions. We also thank the staff of the National Institute of Radiological Sciences for support with the cyclotron operation, radioisotope production, radiosynthesis, and animal experiments. This study was supported by research grants from the Ministry of Education, Culture, Sports, Science and Technology of Japan (Grants-in-Aid 20390349, 21659310), and in part by the Japan China Medical Association.

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The authors declare no competing financial interests.

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Authors and Affiliations

  1. Division of Radiation Safety and Immune Tolerance, National Research Institute for Child Health and Development, 2-10-1 Okura, Setagaya-ku, Tokyo, 157-8535, Japan

    Lin Xie & Xiao-Kang Li

  2. Department of Advanced Technology for Transplantation, Osaka University Graduate School of Medicine, Osaka, Japan

    Lin Xie & Shiro Takahara

  3. Department of Molecular Probes, Molecular Imaging Center, National Institute of Radiological Sciences, 4-9-1 Anagawa, Inage-Ku, Chiba, 263-8555, Japan

    Tomoteru Yamasaki, Joji Yui, Kazunori Kawamura, Katsushi Kumata, Akiko Hatori & Ming-Rong Zhang

  4. Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan

    Tomoteru Yamasaki

  5. Department of Urology, Osaka University Graduate School of Medicine, Osaka, Japan

    Naotsugu Ichimaru & Norio Nonomura

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  1. Lin Xie
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  2. Tomoteru Yamasaki
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  3. Naotsugu Ichimaru
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  9. Ming-Rong Zhang
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  10. Xiao-Kang Li
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Correspondence to Ming-Rong Zhang or Xiao-Kang Li.

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Lin Xie, Tomoteru Yamazaki and Naotsugu Ichimaru contributed equally to this work.

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Xie, L., Yamasaki, T., Ichimaru, N. et al. [11C]DAC-PET for Noninvasively Monitoring Neuroinflammation and Immunosuppressive Therapy Efficacy in Rat Experimental Autoimmune Encephalomyelitis Model. J Neuroimmune Pharmacol 7, 231–242 (2012). https://doi.org/10.1007/s11481-011-9322-3

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