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.
Article and author information
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.
Metrics
-
- 2,189
- views
-
- 340
- downloads
-
- 25
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
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)
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
Further reading
-
- Neuroscience
Control of voluntary limb movement is predominantly attributed to the contralateral motor cortex. However, increasing evidence suggests the involvement of ipsilateral cortical networks in this process, especially in motor tasks requiring bilateral coordination, such as locomotion. In this study, we combined a unilateral thoracic spinal cord injury (SCI) with a cortical neuroprosthetic approach to investigate the functional role of the ipsilateral motor cortex in rat movement through spared contralesional pathways. Our findings reveal that in all SCI rats, stimulation of the ipsilesional motor cortex promoted a bilateral synergy. This synergy involved the elevation of the contralateral foot along with ipsilateral hindlimb extension. Additionally, in two out of seven animals, stimulation of a sub-region of the hindlimb motor cortex modulated ipsilateral hindlimb flexion. Importantly, ipsilateral cortical stimulation delivered after SCI immediately alleviated multiple locomotor and postural deficits, and this effect persisted after ablation of the homologous motor cortex. These results provide strong evidence of a causal link between cortical activation and precise ipsilateral control of hindlimb movement. This study has significant implications for the development of future neuroprosthetic technology and our understanding of motor control in the context of SCI.
-
- Neuroscience
Mice can generate a cognitive map of an environment based on self-motion signals when there is a fixed association between their starting point and the location of their goal.
