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- Title
Activity of a Novel Anti-Inflammatory Agent F-3,6′-dithiopomalidomide as a Treatment for Traumatic Brain Injury.
- Authors
Hsueh, Shih Chang; Scerba, Michael T.; Tweedie, David; Lecca, Daniela; Kim, Dong Seok; Baig, Abdul Mannan; Kim, Yu Kyung; Hwang, Inho; Kim, Sun; Selman, Warren R.; Hoffer, Barry J.; Greig, Nigel H.
- Abstract
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.
- Subjects
BRAIN injuries; ANTI-inflammatory agents; APOLIPOPROTEIN E4; THALIDOMIDE; DRUG discovery; ALZHEIMER'S disease; PARKINSON'S disease
- Publication
Biomedicines, 2022, Vol 10, Issue 10, pN.PAG
- ISSN
2227-9059
- Publication type
Article
- DOI
10.3390/biomedicines10102449