1. A novel PROTAC molecule dBET1 alleviates pathogenesis of experimental autoimmune encephalomyelitis in mice by degrading BRD4.
- Author
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Song Z, Li J, He Y, Wang X, Tian J, and Wu Y
- Subjects
- Animals, Mice, Female, Multiple Sclerosis drug therapy, Proteolysis drug effects, Humans, Lipopolysaccharides, Anti-Inflammatory Agents pharmacology, Anti-Inflammatory Agents therapeutic use, Cells, Cultured, Neurons drug effects, Neurons metabolism, Neurons pathology, Nuclear Proteins metabolism, Bromodomain Containing Proteins, Encephalomyelitis, Autoimmune, Experimental drug therapy, Encephalomyelitis, Autoimmune, Experimental immunology, Mice, Inbred C57BL, Transcription Factors metabolism, Transcription Factors genetics, Astrocytes drug effects, Astrocytes metabolism, Spinal Cord drug effects, Spinal Cord metabolism, Spinal Cord pathology, Spinal Cord immunology
- Abstract
Neuroinflammation and neurodegeneration are hallmarks of multiple sclerosis (MS). Bromodomain-containing protein 4 (BRD4), a bromodomain and extra-terminal domain (BET) protein family member, is indispensable for the transcription of pro-inflammatory genes. Therefore, inhibiting BRD4 may be a prospective therapeutic approach for modulating the inflammatory response and regulating the course of MS. dBET1, a newly synthesized proteolysis-targeting chimera (PROTAC), exhibits effectively degrades of BRD4. However, the precise effects of dBET1 on MS require further investigation. Therefore, we assessed the effect of dBET1 in experimental autoimmune encephalomyelitis (EAE), a typical MS experimental model. Our findings revealed that BRD4 is mainly expressed in astrocytes and neurons of the spinal cords, and is up-regulated in the spinal cords of EAE mice. The dBET1 attenuated lipopolysaccharide-induced expression of astrocytic pro-inflammatory mediators and inhibited deleterious molecular activity in astrocytes. Correspondingly, dBET1, used in preventive and therapeutic settings, alleviated the behavioral symptoms in EAE mice, as demonstrated by decreased demyelination, alleviated leukocyte infiltration, reduced microglial and astrocyte activation, and diminished inflammatory mediator levels. In addition, dBET1 corrected the imbalance in peripheral T cells and protected blood-brain barrier integrity in EAE mice. The underlying mechanism involved suppressing the phosphoinositide-3-kinase/protein kinase B, mitogen-activated protein kinase /extracellular signal-regulated kinase, and nuclear factor kappa B pathways. In summary, our data strongly suggests that dBET1 is a promising treatment option for MS., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)
- Published
- 2024
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