3,6'-Dithiopomalidomide reduces neural loss, inflammation, behavioral deficits in brain injury and microglial activation
- Taipei Medical University, Taiwan
- National Institute on Aging, NIH, United States
- Case Western Reserve University, United States
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.
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Author details
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.
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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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
