1. Neuroscience

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
https://doi.org/10.7554/eLife.54726
Share this article
Cite this article
  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
  13. Nigel H Greig
(2020)
3,6'-Dithiopomalidomide reduces neural loss, inflammation, behavioral deficits in brain injury and microglial activation
eLife 9:e54726.
https://doi.org/10.7554/eLife.54726
  2. Download BibTeX
  3. Download .RIS

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.

Data availability

All data generated or analysed during this study are included in the manuscript and supporting files. Source data files have been provided for all figures.

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)
  4. Version of Record published: July 22, 2020 (version 2)

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.

Metrics

  • 1,850
    Page views
  • 283
    Downloads
  • 18
    Citations

Article citation count generated by polling the highest count across the following sources: Crossref, PubMed Central, Scopus.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  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
  13. Nigel H Greig
(2020)
3,6'-Dithiopomalidomide reduces neural loss, inflammation, behavioral deficits in brain injury and microglial activation
eLife 9:e54726.
https://doi.org/10.7554/eLife.54726

Categories and tags

Research organism

Further reading

    1. Neuroscience

    Landmark-based spatial navigation across the human lifespan

    Marcia Bécu, Denis Sheynikhovich ... Angelo Arleo
    Research Article Updated

    Human spatial cognition has been mainly characterized in terms of egocentric (body-centered) and allocentric (world-centered) wayfinding bhavior. It was hypothesized that allocentric spatial coding, as a special high-level cognitive ability, develops later and deteriorates earlier than the egocentric one throughout lifetime. We challenged this hypothesis by testing the use of landmarks versus geometric cues in a cohort of 96 deeply phenotyped participants, who physically navigated an equiangular Y maze, surrounded by landmarks or an anisotropic one. The results show that an apparent allocentric deficit in children and aged navigators is caused specifically by difficulties in using landmarks for navigation while introducing a geometric polarization of space made these participants as efficient allocentric navigators as young adults. This finding suggests that allocentric behavior relies on two dissociable sensory processing systems that are differentially affected by human aging. Whereas landmark processing follows an inverted-U dependence on age, spatial geometry processing is conserved, highlighting its potential in improving navigation performance across the lifespan.

    1. Neuroscience

    Enteroendocrine cell lineages that differentially control feeding and gut motility

    Marito Hayashi, Judith A Kaye ... Stephen D Liberles
    Research Article Updated

    Enteroendocrine cells are specialized sensory cells of the gut-brain axis that are sparsely distributed along the intestinal epithelium. The functions of enteroendocrine cells have classically been inferred by the gut hormones they release. However, individual enteroendocrine cells typically produce multiple, sometimes apparently opposing, gut hormones in combination, and some gut hormones are also produced elsewhere in the body. Here, we developed approaches involving intersectional genetics to enable selective access to enteroendocrine cells in vivo in mice. We targeted FlpO expression to the endogenous Villin1 locus (in Vil1-p2a-FlpO knock-in mice) to restrict reporter expression to intestinal epithelium. Combined use of Cre and Flp alleles effectively targeted major transcriptome-defined enteroendocrine cell lineages that produce serotonin, glucagon-like peptide 1, cholecystokinin, somatostatin, or glucose-dependent insulinotropic polypeptide. Chemogenetic activation of different enteroendocrine cell types variably impacted feeding behavior and gut motility. Defining the physiological roles of different enteroendocrine cell types provides an essential framework for understanding sensory biology of the intestine.

    1. Biochemistry and Chemical Biology
    2. Neuroscience

    Glia-neuron coupling via a bipartite sialylation pathway promotes neural transmission and stress tolerance in Drosophila

    Hilary Scott, Boris Novikov ... Vladislav Panin
    Research Article

    Modification by sialylated glycans can affect protein functions, underlying mechanisms that control animal development and physiology. Sialylation relies on a dedicated pathway involving evolutionarily conserved enzymes, including CMP-sialic acid synthetase (CSAS) and sialyltransferase (SiaT) that mediate the activation of sialic acid and its transfer onto glycan termini, respectively. In Drosophila, CSAS and DSiaT genes function in the nervous system, affecting neural transmission and excitability. We found that these genes function in different cells: the function of CSAS is restricted to glia, while DSiaT functions in neurons. This partition of the sialylation pathway allows for regulation of neural functions via a glia-mediated control of neural sialylation. The sialylation genes were shown to be required for tolerance to heat and oxidative stress and for maintenance of the normal level of voltage-gated sodium channels. Our results uncovered a unique bipartite sialylation pathway that mediates glia-neuron coupling and regulates neural excitability and stress tolerance.