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3,6'-Dithiopomalidomide reduces neural loss, inflammation, behavioral deficits in brain injury and microglial activation

  1. Chih-Tung Lin
  2. Daniela Lecca
  3. Ling-Yu Yang
  4. Weiming Luo
  5. Michael T Scerba
  6. David Tweedie
  7. Pen-Sen Huang
  8. Yoo-Jin Jung
  9. Dong Seok Kim
  10. Chih-Hao Yang
  11. Barry J Hoffer
  12. Jia-Yi Wang  Is a corresponding author
  13. Nigel H Greig  Is a corresponding author
  1. Taipei Medical University, Taiwan
  2. National Institute on Aging, NIH, United States
  3. Case Western Reserve University, United States
Research Article
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Cite this article as: eLife 2020;9:e54726 doi: 10.7554/eLife.54726

Abstract

Traumatic brain injury (TBI) causes mortality and disability worldwide. It can initiate acute cell death followed by secondary injury induced by microglial activation, oxidative stress, inflammation and autophagy in brain tissue, resulting in cognitive and behavioral deficits. We evaluated a new pomalidomide (Pom) analog, 3,6'-dithioPom (DP), and Pom as immunomodulatory agents to mitigate TBI-induced cell death, neuroinflammation, astrogliosis and behavioral impairments in rats challenged with controlled cortical impact TBI. Both agents significantly reduced the injury contusion volume and degenerating neuron number evaluated histochemically and by MRI at 24 hr and 7 days, with a therapeutic window of 5 hr post-injury. TBI-induced upregulated markers of microglial activation, astrogliosis and the expression of proinflammatory cytokines, iNOS, COX-2, and autophagy-associated proteins were suppressed, leading to an amelioration of behavioral deficits with DP providing greater potency. Complementary animal and cellular studies demonstrated DP and Pom mediated reductions in markers of neuroinflammation and a-synuclein-induced toxicity.

Article and author information

Author details

  1. Chih-Tung Lin

    Graduate Institute of Medical Sciences, Taipei Medical University, Taipei, Taiwan
    Competing interests
    No competing interests declared.
  2. Daniela Lecca

    Translational Gerontology Branch, National Institute on Aging, NIH, Baltimore, United States
    Competing interests
    No competing interests declared.
  3. Ling-Yu Yang

    Graduate Institute of Medical Sciences, Taipei Medical University, Taipei, Taiwan
    Competing interests
    No competing interests declared.
  4. Weiming Luo

    Translational Gerontology Branch, National Institute on Aging, NIH, Baltimore, United States
    Competing interests
    Weiming Luo, NHG, WL and DT are named inventors on patent 8,927,725 and have assigned all their rights to the NIH (US Government), and hence have noownership of DP or other agents within US Patent 8,927,725..
  5. Michael T Scerba

    Translational Gerontology Branch, National Institute on Aging, NIH, Baltimore, United States
    Competing interests
    No competing interests declared.
  6. David Tweedie

    Translational Gerontology Branch, National Institute on Aging, NIH, Baltimore, United States
    Competing interests
    David Tweedie, NHG, WL and DT are named inventors on patent 8,927,725 and have assigned all their rights to the NIH (US Government), and hence have noownership of DP or other agents within US Patent 8,927,725..
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8446-4544
  7. Pen-Sen Huang

    Graduate Institute of Medical Sciences, Taipei Medical University, Taipei, Taiwan
    Competing interests
    No competing interests declared.
  8. Yoo-Jin Jung

    Translational Gerontology Branch, National Institute on Aging, NIH, Baltimore, United States
    Competing interests
    No competing interests declared.
  9. Dong Seok Kim

    Translational Gerontology Branch, National Institute on Aging, NIH, Baltimore, United States
    Competing interests
    No competing interests declared.
  10. Chih-Hao Yang

    Department of Pharmacology, School of Medicine, College of Medicine,, Taipei Medical University, Taipei, Taiwan
    Competing interests
    No competing interests declared.
  11. Barry J Hoffer

    Department of Neurological Surgery, Case Western Reserve University, Cleveland, United States
    Competing interests
    No competing interests declared.
  12. Jia-Yi Wang

    Dept. Neurosurgery & Neuroscience Research Center, Taipei Medical University, Taipei, Taiwan
    For correspondence
    jywang2010@tmu.edu.tw
    Competing interests
    No competing interests declared.
  13. Nigel H Greig

    Translational Gerontology Branch, National Institute on Aging, NIH, Baltimore, United States
    For correspondence
    Greign@grc.nia.nih.gov
    Competing interests
    Nigel H Greig, NHG, WL and DT are named inventors on patent 8,927,725 and have assigned all their rights to the NIH (US Government), and hence have no ownership of DP or other agents within US Patent 8,927,725..
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3032-1468

Funding

National Institutes of Health, NIA, Intramural Research Program (AG000994)

  • Nigel H Greig

National Institutes of Health (AG057025 (R56))

  • Barry J Hoffer

Ministry of Science and Technology, Taiwan (MOST 104-2923-B-038-001-MY3)

  • Jia-Yi Wang

Ministry of Science and Technology, Taiwan (MOST 108-2321-B-038-008)

  • Jia-Yi Wang

Taipei Medical University (DP2-107-21121-01-N-05)

  • Jia-Yi Wang

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All animals were treated according to the International Guidelines for animal research, and the animal use protocols in this study were reviewed and approved by the Institutional Animal Care and Use Committee or Panel (IACUC/IACUP) of either the Intramural Research Program, National Institute on Aging, NIH (protocol No. 331-TGB-2021), or of Taipei Medical University [Protocol number: LAC-2015-0051]. All surgery was performed under appropriate anesthesia, and every effort was made to minimize suffering.

Reviewing Editor

  1. Sonia Garel, Ecole Normale Superieure, France

Publication history

  1. Received: December 24, 2019
  2. Accepted: June 12, 2020
  3. Accepted Manuscript published: June 26, 2020 (version 1)

Copyright

This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.

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