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Imaging toxin-induced neuroinflammation in mice using hyperpolarized 13C magnetic resonance spectroscopy

Lydia M Le Page, Caroline Guglielmetti, Chloé Najac, Brice Tiret, Myriam M Chaumeil
doi: https://doi.org/10.1101/605568
Lydia M Le Page
1Department of Physical Therapy and Rehabilitation Science, University of California San Francisco, San Francisco, CA, United States
2Department of Radiology and Biomedical Imaging, University of California San Francisco, San Francisco, CA, United States
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Caroline Guglielmetti
1Department of Physical Therapy and Rehabilitation Science, University of California San Francisco, San Francisco, CA, United States
2Department of Radiology and Biomedical Imaging, University of California San Francisco, San Francisco, CA, United States
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Chloé Najac
2Department of Radiology and Biomedical Imaging, University of California San Francisco, San Francisco, CA, United States
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Brice Tiret
1Department of Physical Therapy and Rehabilitation Science, University of California San Francisco, San Francisco, CA, United States
2Department of Radiology and Biomedical Imaging, University of California San Francisco, San Francisco, CA, United States
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Myriam M Chaumeil
1Department of Physical Therapy and Rehabilitation Science, University of California San Francisco, San Francisco, CA, United States
2Department of Radiology and Biomedical Imaging, University of California San Francisco, San Francisco, CA, United States
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  • For correspondence: myriam.chaumeil@ucsf.edu
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Abstract

Lipopolysaccharide (LPS) is a commonly used agent for induction of neuroinflammation in preclinical studies. Upon injection, LPS causes activation of microglia and astrocytes, whose metabolism alters to favor glycolysis. Assessing in vivo neuroinflammation and its modulation following therapy remains challenging, and new non-invasive methods allowing for longitudinal monitoring would be greatly valuable. Hyperpolarized (HP) 13C magnetic resonance spectroscopy (MRS) is a promising technique for assessing in vivo metabolism. In addition to applications in oncology, the most commonly used probe of [1-13C] pyruvate has shown potential in assessing neuroinflammation-linked metabolism in mouse models of multiple sclerosis and traumatic brain injury. Here, we wished to investigate LPS-induced neuroinflammatory changes using HP [1-13C] pyruvate and HP 13C urea.

2D chemical shift imaging following simultaneous intravenous injection of HP [1-13C] pyruvate and HP 13C urea was performed at baseline (day 0), day 3 and day 7 post intracranial injection of LPS (n=6) or saline (n=5). Immunofluorescence (IF) analyses were performed for Iba1 (resting and activated microglia/macrophages), GFAP (resting and reactive astrocytes) and CD68 (activated microglia/macrophages).

A significant increase in HP [1-13C] lactate production was observed in the injected (ipsilateral) side at 3 and 7 days of the LPS-treated mouse brain, but not in either the contralateral side or saline-injected animals. HP 13C lactate/pyruvate ratio, without and with normalization to urea, was also significantly increased in the ipsilateral LPS-injected brain at 7 days compared to baseline. IF analyses showed a significant increase in CD68 and GFAP at 3 days, followed by increased numbers of Iba1 and GFAP positive cells at 7 days post-LPS injection.

In conclusion, we can detect LPS-induced changes in the mouse brain using HP 13C MRS, in alignment with increased numbers of microglia/macrophages and astrocytes. This study demonstrates that HP 13C spectroscopy holds much potential for providing non-invasive information on neuroinflammation.

  • Abbreviations

    LPS
    lipopolysaccharide
    HP
    hyperpolarized
    IF
    immunofluorescence
    Iba 1
    ionized calcium binding adaptor molecule 1
    GFAP
    glial fibrillary acidic protein
    CD68
    Cluster of Differentiation 68
    MS
    multiple sclerosis
    TBI
    traumatic brain injury
    NA
    number of averages
    CSI
    chemical shift imaging
    PFA
    paraformaldehyde
  • Copyright 
    The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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    Posted April 11, 2019.
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    Imaging toxin-induced neuroinflammation in mice using hyperpolarized 13C magnetic resonance spectroscopy
    Lydia M Le Page, Caroline Guglielmetti, Chloé Najac, Brice Tiret, Myriam M Chaumeil
    bioRxiv 605568; doi: https://doi.org/10.1101/605568
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    Imaging toxin-induced neuroinflammation in mice using hyperpolarized 13C magnetic resonance spectroscopy
    Lydia M Le Page, Caroline Guglielmetti, Chloé Najac, Brice Tiret, Myriam M Chaumeil
    bioRxiv 605568; doi: https://doi.org/10.1101/605568

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