Activity of a Novel Anti-Inflammatory Agent F-3,6′-dithiopomalidomide as a Treatment for Traumatic Brain Injury
Traumatic brain injury (TBI) is a major risk factor for several neurodegenerative disorders, including Parkinson’s disease (PD) and Alzheimer’s disease (AD). Neuroinflammation is a cause of later secondary cell death following TBI, has the potential to aggravate the initial impact, and provides a th...
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| Format: | Article |
| Language: | English |
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MDPI AG
2022-09-01
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| Series: | Biomedicines |
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| Online Access: | https://www.mdpi.com/2227-9059/10/10/2449 |
| _version_ | 1797475073280442368 |
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| author | Shih Chang Hsueh Michael T. Scerba David Tweedie Daniela Lecca Dong Seok Kim Abdul Mannan Baig Yu Kyung Kim Inho Hwang Sun Kim Warren R. Selman Barry J. Hoffer Nigel H. Greig |
| author_facet | Shih Chang Hsueh Michael T. Scerba David Tweedie Daniela Lecca Dong Seok Kim Abdul Mannan Baig Yu Kyung Kim Inho Hwang Sun Kim Warren R. Selman Barry J. Hoffer Nigel H. Greig |
| author_sort | Shih Chang Hsueh |
| collection | DOAJ |
| description | Traumatic brain injury (TBI) is a major risk factor for several neurodegenerative disorders, including Parkinson’s disease (PD) and Alzheimer’s disease (AD). Neuroinflammation is a cause of later secondary cell death following TBI, has the potential to aggravate the initial impact, and provides a therapeutic target, albeit that has failed to translate into clinical trial success. Thalidomide-like compounds have neuroinflammation reduction properties across cellular and animal models of TBI and neurodegenerative disorders. They lower the generation of proinflammatory cytokines, particularly TNF-α which is pivotal in microglial cell activation. Unfortunately, thalidomide-like drugs possess adverse effects in humans before achieving anti-inflammatory drug levels. We developed F-3,6′-dithiopomalidomide (F-3,6′-DP) as a novel thalidomide-like compound to ameliorate inflammation. F-3,6′-DP binds to cereblon but does not efficiently trigger the degradation of the transcription factors (SALL4, Ikaros, and Aiolos) associated with the teratogenic and anti-proliferative responses of thalidomide-like drugs. We utilized a phenotypic drug discovery approach that employed cellular and animal models in the selection and development of F-3,6’-DP. F-3,6′-DP significantly mitigated LPS-induced inflammatory markers in RAW 264.7 cells, and lowered proinflammatory cytokine/chemokine levels in the plasma and brain of rats challenged with systemic LPS. We subsequently examined immunohistochemical, biochemical, and behavioral measures following controlled cortical impact (CCI) in mice, a model of moderate TBI known to induce inflammation. F-3,6′-DP decreased CCI-induced neuroinflammation, neuronal loss, and behavioral deficits when administered after TBI. F-3,6′-DP represents a novel class of thalidomide-like drugs that do not lower classical cereblon-associated transcription factors but retain anti-inflammatory actions and possess efficacy in the treatment of TBI and potentially longer-term neurodegenerative disorders. |
| first_indexed | 2024-03-09T20:38:57Z |
| format | Article |
| id | doaj.art-7363abdad1cd4e2f96aeea1e980c087f |
| institution | Directory Open Access Journal |
| issn | 2227-9059 |
| language | English |
| last_indexed | 2024-03-09T20:38:57Z |
| publishDate | 2022-09-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Biomedicines |
| spelling | doaj.art-7363abdad1cd4e2f96aeea1e980c087f2023-11-23T23:03:15ZengMDPI AGBiomedicines2227-90592022-09-011010244910.3390/biomedicines10102449Activity of a Novel Anti-Inflammatory Agent F-3,6′-dithiopomalidomide as a Treatment for Traumatic Brain InjuryShih Chang Hsueh0Michael T. Scerba1David Tweedie2Daniela Lecca3Dong Seok Kim4Abdul Mannan Baig5Yu Kyung Kim6Inho Hwang7Sun Kim8Warren R. Selman9Barry J. Hoffer10Nigel H. Greig11Drug Design & Development Section, Translational Gerontology Branch, Intramural Research Program National Institute on Aging, NIH, Baltimore, MD 21224, USADrug Design & Development Section, Translational Gerontology Branch, Intramural Research Program National Institute on Aging, NIH, Baltimore, MD 21224, USADrug Design & Development Section, Translational Gerontology Branch, Intramural Research Program National Institute on Aging, NIH, Baltimore, MD 21224, USADrug Design & Development Section, Translational Gerontology Branch, Intramural Research Program National Institute on Aging, NIH, Baltimore, MD 21224, USAAevisBio, Inc., Gaithersburg, MD 20878, USADepartment of Biological and Biomedical Sciences, Aga Khan University, Karachi 74800, PakistanAevis Bio, Inc., Daejeon 34141, KoreaAevis Bio, Inc., Daejeon 34141, KoreaAevis Bio, Inc., Daejeon 34141, KoreaDepartment of Neurological Surgery, Case Western Reserve University and University Hospitals, Cleveland, OH 44106, USADepartment of Neurological Surgery, Case Western Reserve University and University Hospitals, Cleveland, OH 44106, USADrug Design & Development Section, Translational Gerontology Branch, Intramural Research Program National Institute on Aging, NIH, Baltimore, MD 21224, USATraumatic brain injury (TBI) is a major risk factor for several neurodegenerative disorders, including Parkinson’s disease (PD) and Alzheimer’s disease (AD). Neuroinflammation is a cause of later secondary cell death following TBI, has the potential to aggravate the initial impact, and provides a therapeutic target, albeit that has failed to translate into clinical trial success. Thalidomide-like compounds have neuroinflammation reduction properties across cellular and animal models of TBI and neurodegenerative disorders. They lower the generation of proinflammatory cytokines, particularly TNF-α which is pivotal in microglial cell activation. Unfortunately, thalidomide-like drugs possess adverse effects in humans before achieving anti-inflammatory drug levels. We developed F-3,6′-dithiopomalidomide (F-3,6′-DP) as a novel thalidomide-like compound to ameliorate inflammation. F-3,6′-DP binds to cereblon but does not efficiently trigger the degradation of the transcription factors (SALL4, Ikaros, and Aiolos) associated with the teratogenic and anti-proliferative responses of thalidomide-like drugs. We utilized a phenotypic drug discovery approach that employed cellular and animal models in the selection and development of F-3,6’-DP. F-3,6′-DP significantly mitigated LPS-induced inflammatory markers in RAW 264.7 cells, and lowered proinflammatory cytokine/chemokine levels in the plasma and brain of rats challenged with systemic LPS. We subsequently examined immunohistochemical, biochemical, and behavioral measures following controlled cortical impact (CCI) in mice, a model of moderate TBI known to induce inflammation. F-3,6′-DP decreased CCI-induced neuroinflammation, neuronal loss, and behavioral deficits when administered after TBI. F-3,6′-DP represents a novel class of thalidomide-like drugs that do not lower classical cereblon-associated transcription factors but retain anti-inflammatory actions and possess efficacy in the treatment of TBI and potentially longer-term neurodegenerative disorders.https://www.mdpi.com/2227-9059/10/10/2449pomalidomideimmunomodulatory imide drugs (IMiDs)neuroinflammationtraumatic brain injurycereblon |
| spellingShingle | Shih Chang Hsueh Michael T. Scerba David Tweedie Daniela Lecca Dong Seok Kim Abdul Mannan Baig Yu Kyung Kim Inho Hwang Sun Kim Warren R. Selman Barry J. Hoffer Nigel H. Greig Activity of a Novel Anti-Inflammatory Agent F-3,6′-dithiopomalidomide as a Treatment for Traumatic Brain Injury Biomedicines pomalidomide immunomodulatory imide drugs (IMiDs) neuroinflammation traumatic brain injury cereblon |
| title | Activity of a Novel Anti-Inflammatory Agent F-3,6′-dithiopomalidomide as a Treatment for Traumatic Brain Injury |
| title_full | Activity of a Novel Anti-Inflammatory Agent F-3,6′-dithiopomalidomide as a Treatment for Traumatic Brain Injury |
| title_fullStr | Activity of a Novel Anti-Inflammatory Agent F-3,6′-dithiopomalidomide as a Treatment for Traumatic Brain Injury |
| title_full_unstemmed | Activity of a Novel Anti-Inflammatory Agent F-3,6′-dithiopomalidomide as a Treatment for Traumatic Brain Injury |
| title_short | Activity of a Novel Anti-Inflammatory Agent F-3,6′-dithiopomalidomide as a Treatment for Traumatic Brain Injury |
| title_sort | activity of a novel anti inflammatory agent f 3 6 dithiopomalidomide as a treatment for traumatic brain injury |
| topic | pomalidomide immunomodulatory imide drugs (IMiDs) neuroinflammation traumatic brain injury cereblon |
| url | https://www.mdpi.com/2227-9059/10/10/2449 |
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