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Peripheral benzodiazepine receptor/18 kDa translocator protein positron emission tomography imaging in a rat model of acute brain injury

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Abstract

Objective

The activation of microglia in various brain pathologies is accompanied by an increase in the expression of peripheral benzodiazepine receptor/18 kDa translocator protein (PBR/TSPO). However, whether activated microglia have a neuroprotective or neurotoxic effect on neurons in the brain is yet to be determined. In this study, we investigated the ability of the novel PBR/TSPO ligand FEPPA to detect activated microglia in an animal model of primary neurotoxic microglia activation.

Methods

[18F] FEPPA positron emission tomography (PET) imaging was performed before and after intraperitoneal administration of lipopolysaccharide (LPS) (LPS group) or saline (control group) in a unilateral 6-hydroxydopamine (6-OHDA) lesion rat model of Parkinson’s disease. Images were compared between these groups. After imaging, the brains were collected, and the activated microglia at the disease sites were analyzed by the expression of inflammatory cytokines and immunohistochemistry staining. These results were then comparatively examined with those obtained by PET imaging.

Results

In the unilateral 6-OHDA lesion rat model, the PBR/TSPO PET signal was significantly increased in the LPS group compared with the saline group. As the increased signal was observed 4 h after the injection, we considered it an acute response to brain injury. In the post-imaging pathological examination, activated microglia were found to be abundant at the site where strong signals were detected, and the expression of the inflammatory cytokines TNF-α and IL-1β was increased. Intraperitoneal LPS administration further increased the expression of inflammatory cytokines, and the PBR/TSPO PET signal increased concurrently. The increase in inflammatory cytokine expression correlated with enhanced signal intensity.

Conclusions

PET signal enhancement by PBR/TSPO at the site of brain injury correlated with the activation of microglia and production of inflammatory cytokines. Furthermore, because FEPPA enables the detection of neurotoxic microglia on PET images, we successfully constructed a novel PET detection system that can monitor neurodegenerative diseases.

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Acknowledgements

All the authors disclose to have no potential conflict of interest. This study was approved by the Ethical Committee of in Fujita Health University and Department of Clinical and Experimental Neuroimaging, National Center for Geriatrics and Gerontology and Gerontology. This study was supported by Japan society for the Promotion of Science (JSPS) KAKENHI (21390350) and a Grant from Fujita Health University.

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Authors and Affiliations

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

    Masahiko Nomura & Hiroshi Toyama

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

    Hiromi Suzuki & Makoto Sawada

  3. Department of Management Nutrition, Faculty of Human Life Science, Nagoya University of Economics, 6-11 Uchikubo, Inuyama, Aichi, Japan

    Takashi Yamada

  4. Faculty of Medicine, University of Tsukuba, Tsukuba, Japan

    Kentaro Hatano

  5. PET Centre, Centre for Addiction and Mental Health, Toronto, ON, M5T 1R8, Canada

    Alan A. Wilson

  6. Department of Clinical and Experimental Neuroimaging, National Center for Geriatrics and Gerontology, 7-430 Morioka-cho, Obu, Aichi, 474-8511, Japan

    Kengo Ito

  7. Department of Radiology, National Center for Geriatrics and Gerontology, 7-430 Morioka-cho, Obu, Aichi, 474-8511, Japan

    Kengo Ito

Authors
  1. Masahiko Nomura
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  2. Hiroshi Toyama
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  3. Hiromi Suzuki
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  4. Takashi Yamada
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Correspondence to Masahiko Nomura.

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Nomura, M., Toyama, H., Suzuki, H. et al. Peripheral benzodiazepine receptor/18 kDa translocator protein positron emission tomography imaging in a rat model of acute brain injury. Ann Nucl Med 35, 8–16 (2021). https://doi.org/10.1007/s12149-020-01530-2

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  • DOI: https://doi.org/10.1007/s12149-020-01530-2

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