Targeting neuroinflammation: 3-monothiopomalidomide a new drug candidate to mitigate traumatic brain injury and neurodegeneration

Targeting neuroinflammation: 3-monothiopomalidomide a new drug candidate to mitigate traumatic brain injury and neurodegeneration

Abstract Background Traumatic Brain Injury (TBI) is a major risk factor for neurodegenerative disorders such as Parkinson’s disease (PD) and Alzheimer’s disease (AD), with neuroinflammation playing a critical role in the secondary cell death that exacerbates the initial injury. While targeting neuro...

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Main Authors: Shih Chang Hsueh, Pathik Parekh, Buyandelger Batsaikhan, Neil Vargesson, David Tweedie, Weiming Luo, Chirag N. Patel, Dong Liu, Ross A. McDevitt, Abdul Mannan Baig, Yu Kyung Kim, Sun Kim, Inho Hwang, Juwan Kim, Mee Youn Lee, Anna R. Carta, Warren R. Selman, Barry J. Hoffer, Dong Seok Kim, Nigel H. Greig
Format: Article
Language:English
Published: BMC 2025-06-01
Series:Journal of Biomedical Science
Subjects:
Neuroinflammation
Immunomodulatory imide drugs (IMiDs)
Neurodegeneration
Microglia
Teratogenicity
Pomalidomide
Online Access:https://doi.org/10.1186/s12929-025-01150-w
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Summary:Abstract Background Traumatic Brain Injury (TBI) is a major risk factor for neurodegenerative disorders such as Parkinson’s disease (PD) and Alzheimer’s disease (AD), with neuroinflammation playing a critical role in the secondary cell death that exacerbates the initial injury. While targeting neuroinflammation holds significant therapeutic promise, clinical trials of available anti-inflammatory agents have fallen short. 3-Mono-thiopomalidomide (3-MP), a novel immunomodulatory imide drug (IMiD), was designed to curb inflammation without the adverse effects of traditional IMiDs and was evaluated across models involving neuroinflammation. Methods 3-MP anti-inflammatory activity was evaluated across cellular (RAW 264.7, IMG cells) and mouse studies following lipopolysaccharide (LPS)-challenge (for pro- and anti-inflammatory cytokines/chemokines), and mice subjected to controlled cortical impact (CCI) moderate traumatic brain injury (TBI). 3-MP human cereblon binding, including neosubstrate and molecular modeling evaluation, as well as chicken teratogenicity, ex vivo mouse and human stability studies, and mouse pharmacokinetics were appraised. Results 3-MP binds human cereblon, a key protein in the E3 ubiquitin ligase complex, without triggering downstream cascades leading to thalidomide-like teratogenicity in chicken embryos. 3-MP reduces pro-inflammatory markers in LPS-stimulated mouse macrophage and microglial cell cultures, and lowers pro-inflammatory cytokine/chemokine levels in plasma and brain of mice challenged with systemic LPS without lowering anti-inflammatory IL-10. 3-MP readily enters brain following systemic administration, and achieves a brain/plasma concentration ratio of 0.44–0.47. 3-MP mitigates behavioral impairments and reduces activation of astrocytes and microglia in mice challenged with CCI TBI. Conclusion 3-MP represents a promising new class of thalidomide-like IMiDs with potent anti-inflammatory effects that offers potential for treating TBI and possibly other neurodegenerative diseases possessing a prominent neuroinflammatory component.
ISSN:1423-0127

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